The DOI matches its Crossref record; 131 of the 131 references it cites were found in a registry or an index; 9 of the 172 sources its claims cite were checked for support.
Nicotine is a Selective Pharmacological Chaperone of Acetylcholine Receptor Number and Stoichiometry. Implications for Drug Discovery
Open accessAbstract
The acronym SePhaChARNS, for "selective pharmacological chaperoning of acetylcholine receptor number and stoichiometry," is introduced. We hypothesize that SePhaChARNS underlies classical observations that chronic exposure to nicotine causes "upregulation" of nicotinic receptors (nAChRs). If the hypothesis is proven, (1) SePhaChARNS is the molecular mechanism of the first step in neuroadaptation to chronic nicotine; and (2) nicotine addiction is partially a disease of excessive chaperoning. The chaperone is a pharmacological one, nicotine; and the chaperoned molecules are alpha4beta2* nAChRs. SePhaChARNS may also underlie two inadvertent therapeutic effects of tobacco use: (1) the inverse correlation between tobacco use and Parkinson's disease; and (2) the suppression of seizures by nicotine in autosomal dominant nocturnal frontal lobe epilepsy. SePhaChARNS arises from the thermodynamics of pharmacological chaperoning: ligand binding, especially at subunit interfaces, stabilizes AChRs during assembly and maturation, and this stabilization is most pronounced for the highest-affinity subunit compositions, stoichiometries, and functional states of receptors. Several chemical and pharmacokinetic characteristics render exogenous nicotine a more potent pharmacological chaperone than endogenous acetylcholine. SePhaChARNS is modified by desensitized states of nAChRs, by acid trapping of nicotine in organelles, and by other aspects of proteostasis. SePhaChARNS is selective at the cellular, and possibly subcellular, levels because of variations in the detailed nAChR subunit composition, as well as in expression of auxiliary proteins such as lynx. One important implication of the SePhaChARNS hypothesis is that therapeutically relevant nicotinic receptor drugs could be discovered by studying events in intracellular compartments rather than exclusively at the surface membrane.
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Written from the paper’s full text.
TL;DR
The paper introduces SePhaChARNS—selective pharmacological chaperoning of acetylcholine receptor number and stoichiometry—as a hypothesis for how chronic nicotine upregulates α4β2* nicotinic receptors. It argues this mechanism may explain nicotine addiction, the inverse smoking–Parkinson’s disease association, and ADNFLE seizure suppression, and implies drug discovery should target intracellular ER events.
Key findings
- SePhaChARNS proposes that chronic nicotine acts as a pharmacological chaperone in the endoplasmic reticulum, stabilizing high-affinity α4β2* nAChR stoichiometries; upregulation is described as post-translational, cell-autonomous, and receptor-autonomous. The high- and low-sensitivity α4β2 forms differ by 50- to 100-fold in nicotine EC50 (~1 and ~100 μM), and nicotine shows an EC50 of <100 nM for upregulation in clonal cell lines transfected with α4 and β2 subunits.
- Nicotine differs from ACh in duration and access: nicotine disappears from blood with a half-life of ~120 min, whereas ACh remains near receptors for <1 ms; nicotine permeates membranes and acid-traps in organelles, with pH 6.5 giving a threefold higher organelle concentration and pH 5.5 giving a 30-fold ratio. Nicotine’s EC50 is ~1 μM at (α4)2(β2)3 neuronal receptors versus ~400 μM at (α1)2β1γδ muscle receptors.
- Chronic nicotine cell-selectively upregulates functional α4* nAChRs in VTA GABAergic neurons and the medial perforant path, effects linked to tolerance, locomotor sensitization, and cognitive sensitization. The paper also links SePhaChARNS to Parkinson’s disease protection and ADNFLE, and notes CHRNA5/A3/B4 variants rs16969968 and rs578776 (r² = 0.18) in nicotine dependence, plus lynx1 making α4β2 nAChRs up to 20-fold less sensitive to ACh.
- A major drug-discovery implication is that medically relevant manipulations of α4β2* nAChRs may occur in the ER rather than at the surface membrane, so drugs affecting SePhaChARNS might be discovered by studying intracellular compartments and proteostasis.
Methods
- Design: review/hypothesis paper introducing the acronym SePhaChARNS; it is not a primary experimental study.
- Data or sample: synthesis of published literature and unpublished data from the authors’ laboratories, including cited unpublished results from C. Xiao and H. Lester, submitted work by C. Son et al., and unpublished haplotype data from A. M. Goate, J. Wang, and L. Bierut.
- Main analysis: conceptual and thermodynamic argument linking ligand binding, receptor assembly/maturation, stoichiometry, desensitization, acid trapping, proteostasis, and accessory-subunit/genetic data.
Limitations
- Stated in the paper: the SePhaChARNS hypothesis remains to be proven; several experiments are under way; the complete circuit description is not available; pH values have not been determined for neurons; ADNFLE pathophysiology is not yet understood; and upregulation by nicotine plus a foot-in-the-door blocker remains only a theoretical possibility.
- Stated in the paper: SePhaChARNS probably does not explain withdrawal and may not explain heavy smoking in schizophrenia.
- Evident from the text: the review relies on unpublished or submitted data and narrative synthesis, with no systematic review methods or primary experimental methods reported.
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Claims the paper makes
93 Not checked yet · 53 Own interpretation · 9 No basis given · 4 Supported · 3 Partly supported · 1 Supported so far · accuracy not yet measured
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“This phenomenon probably does not require a circuit but arises from a change in presynaptic properties.”
What the sources say
- Partly supportedcites [5] R. Nashmi, C. Xiao, P. Deshpande, S. Mckinney, S. R. Grady, P. Whiteaker, Q. Huang, T. Mcclure-Begley, J. M. Lindstrom, C. Labarca, A. C. Collins, M. J. Marks, and H. A. Lester. Chronic nicotine cell specifically upregulates functional α4* nicotinic receptors: basis for both tolerance in midbrain and enhanced long-term potentiation in perforant path. J Neurosci. 27:8202–8218 (2007). sourceExperimental — accuracy not yet measured
In “Sensitization to nicotine at glutamatergic synapses suggests a mechanism for cognitive enhancement” (page not provided), the paper says nicotine-dependent potentiation in the perforant path appears explainable by action at a single synapse, with changes in presynaptic axons. It presents the link to cognitive sensitization as a possibility for further investigation, however, and says chronic nicotine may act through more complex circuit changes in other hippocampal regions. The claim overextends the single-synapse finding to cognitive function generally. (LLM, conf=0.85)
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“This upregulation produces higher GABAergic SNr neuron firing rate, even in the absence of nicotine (5).”
What the sources say
- Supportedcites [5] R. Nashmi, C. Xiao, P. Deshpande, S. Mckinney, S. R. Grady, P. Whiteaker, Q. Huang, T. Mcclure-Begley, J. M. Lindstrom, C. Labarca, A. C. Collins, M. J. Marks, and H. A. Lester. Chronic nicotine cell specifically upregulates functional α4* nicotinic receptors: basis for both tolerance in midbrain and enhanced long-term potentiation in perforant path. J Neurosci. 27:8202–8218 (2007). source
The section on firing frequency in GABAergic neurons (page unavailable) reports significantly higher baseline firing in SNR GABAergic neurons from chronically nicotine-treated mice than in saline-treated controls, measured in the absence of nicotine. The authors say these functional effects correspond to the observed receptor upregulation. (LLM, conf=0.93)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Nicotine protects rodent DA neurons agonist toxin-induced cell loss (21–24), but these neuroprotective effects are absent in α4 nAChR knockout (KO) mice (22).”
What the sources say
- Supportedcites [22] R. E. Ryan, S. A. Ross, J. Drago, and R. E. Loiacono. Dose-related neuroprotective effects of chronic nicotine in 6-hydroxydopamine treated rats, and loss of neuroprotection in α4 nicotinic receptor subunit knockout mice. Br J Pharmacol. 132:1650–1656 (2001). source
The Discussion reports that acute nicotine attenuated methamphetamine-induced nigrostriatal damage in wild-type mice, but no significant neuroprotection was detected in α4 knockout mice. It notes a nonsignificant trend toward increased neuron survival, so “absent” refers to the lack of a significant protective effect. (LLM, conf=0.93)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“In experiments conducted since ADNFLE was mapped in 1995, heterologous expression shows that ADNFLE receptors have a gain of function.”
What the sources say
- Partly supportedcites [30] D. Bertrand, F. Picard, S. Le Hellard, S. Weiland, I. Favre, H. Phillips, S. Bertrand, S. F. Berkovic, A. Malafosse, and J. Mulley. How mutations in the nAChRs can cause ADNFLE epilepsy. Epilepsia. 43(Suppl 5):112–122 (2002). sourceExperimental — accuracy not yet measured
The functional studies in Xenopus oocytes (Methods, p. 2) found increased ACh sensitivity across the four mutants. The Discussion (p. 11) says this common trait suggests a gain of receptor function; it does not establish unqualified gain of function for ADNFLE receptors as the claim states. (LLM, conf=0.84)
- Not checked yetcites [31] N. O. Rodrigues-Pinguet, T. J. Pinguet, A. Figl, H. A. Lester, and B. N. Cohen. Mutations linked to autosomal dominant nocturnal frontal lobe epilepsy affect allosteric Ca2+ activation of the α4β2 nicotinic acetylcholine receptor. Mol Pharmacol. 68:487–501 (2005). source
- Partly supportedcites [32] N. Rodrigues-Pinguet, L. Jia, M. Li, A. Figl, A. Klaassen, A. Truong, H.A. Lester, and B.N. Cohen. Five ADNFLE mutations reduce the Ca2+ dependence of the α4β2 acetylcholine response. J Physiol. 550:11–26 (2003). sourceExperimental — accuracy not yet measured
The Abstract reports heterologous expression of ADNFLE-mutant receptors in Xenopus oocytes, and the Discussion proposes that reduced Ca²⁺ sensitivity could produce a net gain of function under particular synaptic conditions. The expression experiments did not directly show a general gain of function; they showed reduced Ca²⁺-induced increases in the ACh response. (LLM, conf=0.86)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Upregulation does not require synaptic transmission or other diffusible extracellular signals.”
What the sources say
- Supportedcites [48] R. Nashmi, and H. Lester. Cell autonomy, receptor autonomy, and thermodynamics in nicotine receptor up-regulation. Biochem Pharmacol. 74:1145–1154 (2007). source
The Discussion describes α4* receptor up-regulation as cell-autonomous: selective receptor activation was sufficient in nearly pure GABAergic cultures, without interactions with other cell types. The Results likewise state that contact with typical presynaptic input cells was unnecessary. Together, these support the claim that synaptic transmission or signals from other cells are not required in the cultured-neuron setting studied. (LLM, conf=0.86)
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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- Supported
In the paper
“Chronic exposure to nicotine increases α4* receptors on glutamatergic axons of the medial perforant path, which consists of projections from the entorhinal cortex to the dentate gyrus.”
What the sources say
- Not checked yetcites [5] R. Nashmi, C. Xiao, P. Deshpande, S. Mckinney, S. R. Grady, P. Whiteaker, Q. Huang, T. Mcclure-Begley, J. M. Lindstrom, C. Labarca, A. C. Collins, M. J. Marks, and H. A. Lester. Chronic nicotine cell specifically upregulates functional α4* nicotinic receptors: basis for both tolerance in midbrain and enhanced long-term potentiation in perforant path. J Neurosci. 27:8202–8218 (2007). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“In hippocampal slices from chronically treated animals, acute exposure to nicotine during tetanic stimuli lowers the threshold for induction of long-term potentiation in the medial perforant path.”
What the sources say
- Not checked yetcites [5] R. Nashmi, C. Xiao, P. Deshpande, S. Mckinney, S. R. Grady, P. Whiteaker, Q. Huang, T. Mcclure-Begley, J. M. Lindstrom, C. Labarca, A. C. Collins, M. J. Marks, and H. A. Lester. Chronic nicotine cell specifically upregulates functional α4* nicotinic receptors: basis for both tolerance in midbrain and enhanced long-term potentiation in perforant path. J Neurosci. 27:8202–8218 (2007). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“We find increased sensitivity both in the somata and in the synaptic terminals; the latter is assessed by recordings on the downstream target, SNc dopaminergic neurons.”
What the sources say
- Not checked yetcites C. Xiao and H. Lester, unpublished
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Our recent experiments show that five ADNFLE receptors have an additional common abnormality. The intracellular pool of mutant receptors is shifted toward the (α4)3(β2)2 stoichiometry.”
What the sources say
- Not checked yetcites C. Son, F. Moss, B. N. Cohen, H. A. Lester, submitted
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Treatment for 24 h with nicotine reverses this abnormality, bringing the stoichiometry to approximately WT levels (C. Son, F. Moss, B. N. Cohen, H. A. Lester, submitted).”
What the sources say
- Not checked yetcites C. Son, F. Moss, B. N. Cohen, H. A. Lester, submitted
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Our experiments reveal that chronic nicotine upregulates the function of α4β2* nAChRs on dopaminergic terminals.”
What the sources say
- Not checked yetcites C. Xiao and H. Lester, unpublished
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In recent experiments (C. Xiao and H. Lester, unpublished), we have confirmed and extended observations that chronic nicotine upregulates nAChR sensitivity in GABAergic neurons of mouse SNr.”
What the sources say
- Not checked yetcites C. Xiao and H. Lester, unpublished
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“These effects vanish in α4 knockout mice (C. Xiao and H. Lester, unpublished.”
What the sources say
- Not checked yetcites C. Xiao and H. Lester, unpublished
plain- Asserted: passes — The authors put it forward as true.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Importantly for these concepts, upregulation is also observed in clonal cell lines transfected with nAChRs.”
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“We extended classical genetic concepts to state that upregulation displays “cell autonomy”. This means that upregulation occurs in the very cell where nicotine acts on the appropriate receptors (48).”
What the sources say
- Not checked yetcites [48] R. Nashmi, and H. Lester. Cell autonomy, receptor autonomy, and thermodynamics in nicotine receptor up-regulation. Biochem Pharmacol. 74:1145–1154 (2007). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“A-85380 is nearly as membrane-permeant as nicotine itself (Table 1)”
What the sources say
- Not checked yetcites Table 1
plain- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“that the upregulated receptors are probably active rather than desensitized (4,5);”
What the sources say
- Not checked yetcites [4] H. N. Nguyen, B. A. Rasmussen, and D. C. Perry. Binding and functional activity of nicotinic cholinergic receptors in selected rat brain regions are increased following long-term but not short-term nicotine treatment. J Neurochem. 90:40–49 (2004). source
- Not checked yetcites [5] R. Nashmi, C. Xiao, P. Deshpande, S. Mckinney, S. R. Grady, P. Whiteaker, Q. Huang, T. Mcclure-Begley, J. M. Lindstrom, C. Labarca, A. C. Collins, M. J. Marks, and H. A. Lester. Chronic nicotine cell specifically upregulates functional α4* nicotinic receptors: basis for both tolerance in midbrain and enhanced long-term potentiation in perforant path. J Neurosci. 27:8202–8218 (2007). source
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“But increasing evidence suggests that upregulation of high-sensitivity nAChRs is, at least partially, the basis for several key biological results of chronic nicotine administration: tolerance, locomotor sensitization, and cognitive sensitization (5,10–12).”
What the sources say
- Not checked yetcites [5] R. Nashmi, C. Xiao, P. Deshpande, S. Mckinney, S. R. Grady, P. Whiteaker, Q. Huang, T. Mcclure-Begley, J. M. Lindstrom, C. Labarca, A. C. Collins, M. J. Marks, and H. A. Lester. Chronic nicotine cell specifically upregulates functional α4* nicotinic receptors: basis for both tolerance in midbrain and enhanced long-term potentiation in perforant path. J Neurosci. 27:8202–8218 (2007). source
- Not checked yetcites [10] B. Buisson, and D. Bertrand. Nicotine addiction: the possible role of functional upregulation. Trends Pharmacol Sci. 23:130–136 (2002). source
- Not checked yetcites [11] C. L. Gentry, and R. J. Lukas. Regulation of nicotinic acetylcholine receptor numbers and function by chronic nicotine exposure. Curr Drug Targets CNS Neurol Disord. 1:359–385 (2002). source
- Not checked yetcites [12] A. Tapper, S. Mckinney, M. Marks, and H. Lester. Nicotine responses in hypersensitive and knockout α4 mice account for tolerance to both hypothermia and locomotor suppression in wild-type mice. Physiol Genomics. 3:422–428 (2007). source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“This instance of cell selective (“Se”) numerical upregulation (“N”) of functional receptors provides a plausible explanation for another effect of chronic nicotine: sensitization of cognitive function in forebrain.”
What the sources say
- Not checked yetcites [5] R. Nashmi, C. Xiao, P. Deshpande, S. Mckinney, S. R. Grady, P. Whiteaker, Q. Huang, T. Mcclure-Begley, J. M. Lindstrom, C. Labarca, A. C. Collins, M. J. Marks, and H. A. Lester. Chronic nicotine cell specifically upregulates functional α4* nicotinic receptors: basis for both tolerance in midbrain and enhanced long-term potentiation in perforant path. J Neurosci. 27:8202–8218 (2007). source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“and that the extent of upregulation is region- and cell-selective (5) (major reasons for the initial “Se”).”
What the sources say
- Not checked yetcites [5] R. Nashmi, C. Xiao, P. Deshpande, S. Mckinney, S. R. Grady, P. Whiteaker, Q. Huang, T. Mcclure-Begley, J. M. Lindstrom, C. Labarca, A. C. Collins, M. J. Marks, and H. A. Lester. Chronic nicotine cell specifically upregulates functional α4* nicotinic receptors: basis for both tolerance in midbrain and enhanced long-term potentiation in perforant path. J Neurosci. 27:8202–8218 (2007). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“These data suggest that alterations in dopaminergic signaling due to chronic nicotine are due to receptor upregulation within GABAergic VTA neurons,”
What the sources say
- Not checked yetcites [5] R. Nashmi, C. Xiao, P. Deshpande, S. Mckinney, S. R. Grady, P. Whiteaker, Q. Huang, T. Mcclure-Begley, J. M. Lindstrom, C. Labarca, A. C. Collins, M. J. Marks, and H. A. Lester. Chronic nicotine cell specifically upregulates functional α4* nicotinic receptors: basis for both tolerance in midbrain and enhanced long-term potentiation in perforant path. J Neurosci. 27:8202–8218 (2007). source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Nicotine protects rodent DA neurons agonist toxin-induced cell loss (21–24), but these neuroprotective effects are absent in α4 nAChR knockout (KO) mice (22).”
What the sources say
- Not checked yetcites [21] M. Khwaja, A. Mccormack, J. M. Mcintosh, D. A. Di Monte, and M. Quik. Nicotine partially protects against paraquat-induced nigrostriatal damage in mice; link to α6β2* nAChRs. J Neurochem. 100:180–190 (2007). source
- Not checked yetcites [22] R. E. Ryan, S. A. Ross, J. Drago, and R. E. Loiacono. Dose-related neuroprotective effects of chronic nicotine in 6-hydroxydopamine treated rats, and loss of neuroprotection in α4 nicotinic receptor subunit knockout mice. Br J Pharmacol. 132:1650–1656 (2001). source
- Not checked yetcites [23] A. M. Janson, K. Fuxe, E. Sundstrom, L. F. Agnati, and M. Goldstein. Chronic nicotine treatment partly protects against the 1-methyl-4-phenyl-2,3,6-tetrahydropyridine-induced degeneration of nigrostriatal dopamine neurons in the black mouse. Acta Physiol Scand. 132:589–591 (1988). source
- Not checked yetcites [24] G. Costa, J. A. Abin-Carriquiry, and F. Dajas. Nicotine prevents striatal dopamine loss produced by 6-hydroxydopamine lesion in the substantia nigra. Brain Res. 888:336–342 (2001). source
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“SePhaChARNS probably does not explain withdrawal (13,14),”
What the sources say
- Not checked yetcites [13] R. Salas, F. Pieri, and M. De Biasi. Decreased signs of nicotine withdrawal in mice null for the β4 nicotinic acetylcholine receptor subunit. J Neurosci. 24:10035–10039 (2004). source
- Not checked yetcites [14] K. J. Jackson, B. R. Martin, J. P. Changeux, and M. I. Damaj. Differential role of nicotinic acetylcholine receptor subunits in physical and affective nicotine withdrawal signs. J Pharmacol Exp Ther. 325:302–312 (2008). source
hedged- Asserted: passes — The authors put it forward as true.
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In the paper
“Thus, the upregulated presynaptic α4* receptors in this pathway are also functional.”
What the sources say
- Not checked yetcites [5] R. Nashmi, C. Xiao, P. Deshpande, S. Mckinney, S. R. Grady, P. Whiteaker, Q. Huang, T. Mcclure-Begley, J. M. Lindstrom, C. Labarca, A. C. Collins, M. J. Marks, and H. A. Lester. Chronic nicotine cell specifically upregulates functional α4* nicotinic receptors: basis for both tolerance in midbrain and enhanced long-term potentiation in perforant path. J Neurosci. 27:8202–8218 (2007). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Pioneering results showed that when rodents are exposed to chronic nicotine, the level of [3H]-nicotine binding increases (1,2), probably denoting increased receptor numbers (“N” in SePhaChARNS).”
What the sources say
- Not checked yetcites [1] R. D. Schwartz, and K. J. Kellar. Nicotinic cholinergic receptor binding sites in the brain: regulation in vivo. Science. 220:214–216 (1983). source
- Not checked yetcites [2] M. J. Marks, J. B. Burch, and A. C. Collins. Effects of chronic nicotine infusion on tolerance development and nicotinic receptors. J Pharmacol Exp Ther. 226:817–825 (1983). source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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None of the sources cited for this claim have been checked yet.
In the paper
“Human smokers also show increased levels of nAChRs in functional magnetic resonance imaging and post mortem measurements (6–9).”
What the sources say
- Not checked yetcites [6] C. R. Breese, M. J. Marks, J. Logel, C. E. Adams, B. Sullivan, A. C. Collins, and S. Leonard. Effect of smoking history on [3H]nicotine binding in human postmortem brain. J Pharmacol Exl Ther. 282:7–13 (1997). source
- Not checked yetcites [7] M. Mamede, K. Ishizu, M. Ueda, T. Mukai, Y. Iida, H. Kawashima, H. Fukuyama, K. Togashi, and H. Saji. Temporal change in human nicotinic acetylcholine receptor after smoking cessation: 5IA SPECT study. J Nucl Med. 48:1829–1835 (2007). source
- Not checked yetcites [8] D. C. Perry, M. I. Davila-Garcia, C. A. Stockmeier, and K. J. Kellar. Increased nicotinic receptors in brains from smokers: membrane binding and autoradiography studies. J Pharmacol Exp Ther. 289:1545–1552 (1999). source
- Not checked yetcites [9] J. K. Staley, S. Krishnan-Sarin, K. P. Cosgrove, E. Krantzler, E. Frohlich, E. Perry, J. A. Dubin, K. Estok, E. Brenner, R. M. Baldwin, G. D. Tamagnan, J. P. Seibyl, P. Jatlow, M. R. Picciotto, E. D. London, S. O'malley, and C. H. Van Dyck. Human tobacco smokers in early abstinence have higher levels of β2* nicotinic acetylcholine receptors than nonsmokers. J Neurosci. 26:8707–8714 (2006). source
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In the paper
“First, nicotine can desensitize receptors; second, nicotine can permeate into cells, as described in the next section.”
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Therefore a log P value more positive than −1 implies reasonable membrane permeability, and consequently, the physical presence, at least, to interact with intracellular receptors.”
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In the paper
“Therefore, most of the drug is nonionized in the blood and CSF.”
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- The authors state this as an assumption: All drugs in Table I may be assumed to have pKa values between 7.4 and 8.
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In the paper
“First, nicotine can desensitize receptors; second, nicotine can permeate into cells, as described in the next section.”
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“On the other hand, ACh is hydrolyzed by acetylcholinesterase, which has a turnover rate of ~104/s (36).”
What the sources say
- Not checked yetcites [36] L. Gyermek. New local anesthetic agents. Anesthesiology. 85:226–227 (1996). source
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In the paper
“Other data show that the mutant receptors are less sensitive than WT receptors to decreased external Ca2+ (31,32).”
What the sources say
- Not checked yetcites [31] N. O. Rodrigues-Pinguet, T. J. Pinguet, A. Figl, H. A. Lester, and B. N. Cohen. Mutations linked to autosomal dominant nocturnal frontal lobe epilepsy affect allosteric Ca2+ activation of the α4β2 nicotinic acetylcholine receptor. Mol Pharmacol. 68:487–501 (2005). source
- Not checked yetcites [32] N. Rodrigues-Pinguet, L. Jia, M. Li, A. Figl, A. Klaassen, A. Truong, H.A. Lester, and B.N. Cohen. Five ADNFLE mutations reduce the Ca2+ dependence of the α4β2 acetylcholine response. J Physiol. 550:11–26 (2003). source
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In the paper
“Combined with the non-effect of chronic nicotine on somatodendritic α4β2* nAChRs in SNc dopaminergic neurons, the data suggest a subcellular selectivity of nAChR upregulation, in addition to previously defined selectivity in nAChR subtypes, brain regions, and neuronal cell types.”
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In the paper
“Therefore, most simulations of synaptic transmission conclude that ACh remains near receptors for <1 ms (37,38).”
What the sources say
- Not checked yetcites [37] J. C. Wathey, M. N. Nass, and H. A. Lester. Numerical reconstruction of the quantal event at nicotinic synapses. Biophys. J. 27:145–164 (1979). source
- Not checked yetcites [38] T. M. Bartol, B. R. Land, E. E. Salpeter, and M. M. Salpeter. Monte-Carlo simulation of miniature end-plate current generation in the vertebrate neuromuscular junction. Biophys. J. 59:1290–1307 (1991). source
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In the paper
“autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), which has at least six missense alleles in the α4 or β2 subunits (27–29).”
What the sources say
- Not checked yetcites [27] O. K. Steinlein, J. C. Mulley, P. Propping, R. H. Wallace, H. A. Phillips, G. R. Sutherland, I. E. Scheffer, and S. F. Berkovic. A missense mutation in the neuronal nicotinic acetylcholine receptor α4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy. Nat Genet. 11:201–203 (1995). source
- Not checked yetcites [28] J. O. Willoughby, K. J. Pope, and V. Eaton. Nicotine as an antiepileptic agent in ADNFLE: an N-of-one study. Epilepsia. 44:1238–1240 (2003). source
- Not checked yetcites [29] E. Brodtkorb, and F. Picard. Tobacco habits modulate autosomal dominant nocturnal frontal lobe epilepsy. Epilepsy Behav. 9:515–520 (2006). source
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In the paper
“Evidently, chronic nicotine selectively upregulates α4β2* nAChRs in components of the nigrostriatal dopaminergic pathway.”
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In the paper
“This difference arises because nicotine makes a cation-π interaction with a Trp residue in loop B of the α4 subunit, and a hydrogen bond with the backbone carbonyl group of the peptide bond between this residue and the adjacent downstream residue (44).”
What the sources say
- Not checked yetcites [44] X. X. Xiu, N. Puskar, J. Shanata, H. A. Lester, and D. A. Dougherty. Nicotine binding to brain receptors requires a strong cation-π interaction Nature. (in press) (2009). source
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In the paper
“Thus, receptor upregulation by nicotine cannot be taken as proof that upregulation occurs primarily because of interactions at surface receptors.”
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In the paper
“A strong aspect of the SePhaChARNS idea is that nicotine acts at an intracellular locus, not at the surface membrane.”
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In the paper
“Some data show that the mutant receptors have lower EC50 values than WT receptors (30).”
What the sources say
- Not checked yetcites [30] D. Bertrand, F. Picard, S. Le Hellard, S. Weiland, I. Favre, H. Phillips, S. Bertrand, S. F. Berkovic, A. Malafosse, and J. Mulley. How mutations in the nAChRs can cause ADNFLE epilepsy. Epilepsia. 43(Suppl 5):112–122 (2002). source
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In the paper
“However, in experiments with clonal cell lines, ACh, and other quaternary amine agonists do penetrate into intracellular organelles within ~3 h, albeit much more slowly than nicotine (39).”
What the sources say
- Not checked yetcites [39] A. Kuryatov, J. Luo, J. Cooper, and J. Lindstrom. Nicotine acts as a pharmacological chaperone to up-regulate human α4β2 acetylcholine receptors. Mol Pharmacol. 68:1839–1851 (2005). source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Whether the high-affinity states have open or closed channels would matter little.”
hedged- Asserted: passes — The authors put it forward as true.
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In the paper
“In previous studies on isolated cells, both agonists and antagonists can upregulate receptors (50,52,54,58,59).”
What the sources say
- Not checked yetcites [50] J. Sallette, S. Pons, A. Devillers-Thiery, M. Soudant, L. Prado De Carvalho, J. P. Changeux, and P. J. Corringer. Nicotine upregulates its own receptors through enhanced intracellular maturation. Neuron. 46:595–607 (2005). source
- Not checked yetcites [52] Y. F. Vallejo, B. Buisson, D. Bertrand, and W. N. Green. Chronic nicotine exposure upregulates nicotinic receptors by a novel mechanism. J Neurosci. 25:5563–5572 (2005). source
- Not checked yetcites [54] T. Darsow, T. K. Booker, J. C. Pina-Crespo, and S. F. Heinemann. Exocytic trafficking is required for nicotine-induced up-regulation of α4β2 nicotinic acetylcholine receptors. J Biol Chem. 280:18311–18320 (2005). source
- Not checked yetcites [58] J. Sallette, S. Bohler, P. Benoit, M. Soudant, S. Pons, N. Le Novere, J. P. Changeux, and P. J. Corringer. An extracellular protein microdomain controls up-regulation of neuronal nicotinic acetylcholine receptors by nicotine. J Biol Chem. 279:18767–18775 (2004). source
- Not checked yetcites [59] M. Kishi, and J. H. Steinbach. Role of the agonist binding site in up-regulation of neuronal nicotinic α4β2 receptors. Mol Pharmacol. 70:2037–2044 (2006). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The thermodynamic reasoning implies that micromolar nicotine concentrations preferentially stabilize and therefore preferentially up-regulate the high- but not the low-sensitivity form of the pentamer.”
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“This is, of course, the fundamental mechanism by which SePhaChARNS allows nicotine to select for high-affinity binding states.”
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Thus, upregulation by the combination of nicotine plus a foot-in-the-door blocker remains only a theoretical possibility at present.”
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In the paper
“In summary, desensitization is one set of conformational states that increase the thermodynamic driving force for SePhaChARNS (48).”
What the sources say
- Not checked yetcites [48] R. Nashmi, and H. Lester. Cell autonomy, receptor autonomy, and thermodynamics in nicotine receptor up-regulation. Biochem Pharmacol. 74:1145–1154 (2007). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“First, desensitization is somewhat more prevalent for cation channels (e.g., nAChRs) than for anion channels (e.g., GABA and glycine receptors).”
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“These considerations explain how nicotine exhibits an EC50 of <100 nM for upregulation in clonal cell lines transfected with α4 and β2 subunits (51).”
What the sources say
- Not checked yetcites [51] P. Tumkosit, A. Kuryatov, J. Luo, and J. Lindstrom. β3 subunits promote expression and nicotine-induced up-regulation of human nicotinic α6* nicotinic acetylcholine receptors expressed in transfected cell lines. Mol Pharmacol. 70:1358–1368 (2006). source
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In the paper
“A clear aspect of SePhaChARNS is that the basic molecular interaction that causes upregulation takes place within the endoplasmic reticulum rather than at the cell surface.”
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Nicotinic receptors are upregulated by quaternary ammonium agonists including simple tetramethylammonium and carbachol.”
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“We summarized these findings with the term “receptor autonomy” because activation of no other nicotinic receptors appears necessary (48).”
What the sources say
- Not checked yetcites [48] R. Nashmi, and H. Lester. Cell autonomy, receptor autonomy, and thermodynamics in nicotine receptor up-regulation. Biochem Pharmacol. 74:1145–1154 (2007). source
hedged- Asserted: passes — The authors put it forward as true.
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In the paper
“however, as discussed above, it is more likely that the quaternary drugs have sufficient membrane permeability to allow intracellular actions at the rather high concentrations (0.1–1 mM) that produce upregulation (50,65,66).”
What the sources say
- Not checked yetcites [50] J. Sallette, S. Pons, A. Devillers-Thiery, M. Soudant, L. Prado De Carvalho, J. P. Changeux, and P. J. Corringer. Nicotine upregulates its own receptors through enhanced intracellular maturation. Neuron. 46:595–607 (2005). source
- Not checked yetcites [65] P. Whiteaker, C. G. Sharples, and S. Wonnacott. Agonist-induced up-regulation of α4β2 nicotinic acetylcholine receptors in M10 cells: pharmacological and spatial definition. Mol Pharmacol. 53:950–962 (1998). source
- Not checked yetcites [66] X. Peng, V. Gerzanich, R. Anand, P. J. Whiting, and J. Lindstrom. Nicotine-induced increase in neuronal nicotinic receptors results from a decrease in the rate of receptor turnover. Mol Pharmacol. 46:523–530 (1994). source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“it is not surprising that the latter has no effect on nicotine-induced upregulation in animals (63).”
What the sources say
- Not checked yetcites [63] H. El-Bizri, and P. B. Clarke. Regulation of nicotinic receptors in rat brain following quasi-irreversible nicotinic blockade by chlorisondamine and chronic treatment with nicotine. Br J Pharmacol. 113:917–925 (1994). source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“The α4β2 receptors exist in a mixed population whose nicotine EC50 values differ by 50- to 100-fold (70–73) (~1 and ~100 μM).”
What the sources say
- Not checked yetcites [70] M. Gopalakrishnan, L. M. Monteggia, D. J. Anderson, E. J. Molinari, M. Piattoni-Kaplan, D. Donnelly-Roberts, S. P. Arneric, and J. P. Sullivan. Stable expression, pharmacologic properties and regulation of the human neuronal nicotinic acetylcholine α4β2 receptor. J Pharmacol Exp Ther. 276:289–297 (1996). source
- Not checked yetcites [71] M. J. Marks, P. Whiteaker, J. Calcaterra, J. A. Stitzel, A. E. Bullock, S. R. Grady, M. R. Picciotto, J. P. Changeux, and A. C. Collins. Two pharmacologically distinct components of nicotinic receptor-mediated rubidium efflux in mouse brain require the β2 subunit. J Pharmacol Exp Ther. 289:1090–1103 (1999). source
- Not checked yetcites [72] B. Buisson, and D. Bertrand. Chronic exposure to nicotine upregulates the human α4β2 nicotinic acetylcholine receptor function. J Neurosci. 21:1819–1829 (2001). source
- Not checked yetcites [73] R. Nashmi, M. E. Dickinson, S. Mckinney, M. Jareb, C. Labarca, S. E. Fraser, and H. A. Lester. Assembly of α4β2 nicotinic acetylcholine receptors assessed with functional fluorescently labeled subunits: effects of localization, trafficking, and nicotine-induced upregulation in clonal mammalian cells and in cultured midbrain neurons. J Neurosci. 23:11554–11567 (2003). source
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In the paper
“These considerations explain how DHβE upregulates receptors.”
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“On the other hand, ACh makes the cation-π bond equally strongly with the (α4)2(β2)3 neuronal receptor and with (α1)2β1γδ muscle receptors.”
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Nicotine’s characteristics described previously, however, allow it to interact with receptors, both intracellular and surface-exposed, for many minutes.”
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“This is equal to the state of tightest binding.”
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Evidence is accumulating to support Lindstrom’s proposal that nicotine acts as pharmacological chaperone for nascent nAChRs (39).”
What the sources say
- Not checked yetcites [39] A. Kuryatov, J. Luo, J. Cooper, and J. Lindstrom. Nicotine acts as a pharmacological chaperone to up-regulate human α4β2 acetylcholine receptors. Mol Pharmacol. 68:1839–1851 (2005). source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Once in organelles, A-85380 would compete with nicotine at nAChR binding sites that face the lumen of these organelles.”
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Acid trapping produces concentrations of nicotine many times higher than the smoked extracellular concentration, within the vesicles of the secretory pathway.”
What the sources say
- Not checked yetcites [77] J. W. Putney Jr., and J. F. Borzelleca. On the mechanisms of [14C]nicotine distribution in rat submaxillary gland in vitro. J Pharmacol Exp Ther. 178:180–191 (1971). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“It is now understood that nicotine actually concentrates by many more fold, in the small volume occupied by acidic organelles.”
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, we expect that intracellular receptors are, indeed, mostly desensitized when a person smokes.”
hedgeddirect- Asserted: passes — The authors put it forward as true.
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- The authors state this as an assumption: The assembly and function of receptors within the secretory pathway is approximately normal.
In the paper
“However, it is quite likely that the covalent modifications during endoplasmic reticulum-associated degradation (ERAD) and ER exit do amplify the kinetically based effects of SePhaChARNS (48).”
What the sources say
- Not checked yetcites [48] R. Nashmi, and H. Lester. Cell autonomy, receptor autonomy, and thermodynamics in nicotine receptor up-regulation. Biochem Pharmacol. 74:1145–1154 (2007). source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This acid trapping would not occur for quaternary amines.”
hedged- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“it does not strongly affect the function of surface receptors”
boosted- Asserted: passes — The authors put it forward as true.
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- The authors state this as an assumption: Surface receptors recover from desensitization within a matter of minutes after exposure to extracellular nicotine.
None of the sources cited for this claim have been checked yet.
In the paper
“The most compelling evidence for risk variants contributing to smoking behavior was in the CHRNA5/A3/B4 gene cluster, which encodes the α5, α3, and β4 subunits.”
What the sources say
- Not checked yetcites [90] L. J. Bierut, P. A. Madden, N. Breslau, E. O. Johnson, D. Hatsukami, O. F. Pomerleau, G. E. Swan, J. Rutter, S. Bertelsen, L. Fox, D. Fugman, A. M. Goate, A. L. Hinrichs, K. Konvicka, N. G. Martin, G. W. Montgomery, N. L. Saccone, S. F. Saccone, J. C. Wang, G. A. Chase, J. P. Rice, and D. G. Ballinger. Novel genes identified in a high-density genome wide association study for nicotine dependence. Hum Mol Genet. 16:24–35 (2007). source
- Not checked yetcites [91] S. F. Saccone, A. L. Hinrichs, N. L. Saccone, G. A. Chase, K. Konvicka, P. A. Madden, N. Breslau, E. O. Johnson, D. Hatsukami, O. Pomerleau, G. E. Swan, A. M. Goate, J. Rutter, S. Bertelsen, L. Fox, D. Fugman, N. G. Martin, G. W. Montgomery, J. C. Wang, D. G. Ballinger, J. P. Rice, and L. J. Bierut. Cholinergic nicotinic receptor genes implicated in a nicotine dependence association study targeting 348 candidate genes with 3713 SNPs. Human Molecular Genetics. 16:36–49 (2007). source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“A similar state would apply to receptors endocytosed into the acidic vesicles of the endocytic pathway.”
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- The authors state this as an assumption: The assembly and function of receptors within the secretory pathway is approximately normal.
In the paper
“Although many neuronal cell types express α4β2* receptors, cell types vary substantially in their repertoire of additional expressed subunits (88).”
What the sources say
- Not checked yetcites [88] C. Gotti, M. Zoli, and F. Clementi. Brain nicotinic acetylcholine receptors: native subtypes and their relevance. Trends Pharmacol Sci. 27:482–491 (2006). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“The replicated nicotine dependence loci tagged by rs16969968 (96,100–102) and rs578776 (101,103) have also been reported to influence lung cancer risk in several genome-wide association studies.”
What the sources say
- Not checked yetcites [96] T. E. Thorgeirsson, F. Geller, P. Sulem, T. Rafnar, A. Wiste, K. P. Magnusson, A. Manolescu, G. Thorleifsson, H. Stefansson, A. Ingason, S. N. Stacey, J. T. Bergthorsson, S. Thorlacius, J. Gudmundsson, T. Jonsson, M. Jakobsdottir, J. Saemundsdottir, O. Olafsdottir, L. J. Gudmundsson, G. Bjornsdottir, K. Kristjansson, H. Skuladottir, H. J. Isaksson, T. Gudbjartsson, G. T. Jones, T. Mueller, A. Gottsater, A. Flex, K. K. Aben, F. De Vegt, P. F. Mulders, D. Isla, M. J. Vidal, L. Asin, B. Saez, L. Murillo, T. Blondal, H. Kolbeinsson, J. G. Stefansson, I. Hansdottir, V. Runarsdottir, R. Pola, B. Lin source
- Not checked yetcites [100] C. I. Amos, X. Wu, P. Broderick, I. P. Gorlov, J. Gu, T. Eisen, Q. Dong, Q. Zhang, X. Gu, J. Vijayakrishnan, K. Sullivan, A. Matakidou, Y. Wang, G. Mills, K. Doheny, Y. Y. Tsai, W. V. Chen, S. Shete, M. R. Spitz, and R. S. Houlston. Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1. Nat Genet. (2008). source
- Not checked yetcites [101] R. J. Hung, J. D. Mckay, V. Gaborieau, P. Boffetta, M. Hashibe, D. Zaridze, A. Mukeria, N. Szeszenia-Dabrowska, J. Lissowska, P. Rudnai, E. Fabianova, D. Mates, V. Bencko, L. Foretova, V. Janout, C. Chen, G. Goodman, J. K. Field, T. Liloglou, G. Xinarianos, A. Cassidy, J. Mclaughlin, G. Liu, S. Narod, H. E. Krokan, F. Skorpen, M. B. Elvestad, K. Hveem, L. Vatten, J. Linseisen, F. Clavel-Chapelon, P. Vineis, H. B. Bueno-De-Mesquita, E. Lund, C. Martinez, S. Bingham, T. Rasmuson, P. Hainaut, E. Riboli, W. Ahrens, S. Benhamou, P. Lagiou, D. Trichopoulos, I. Holcatova, F. Merletti, K. Kjaerheim, A source
- Not checked yetcites [102] P. Liu, H. G. Vikis, D. Wang, Y. Lu, Y. Wang, A. G. Schwartz, S. M. Pinney, P. Yang, M. De Andrade, G. M. Petersen, J. S. Wiest, P. R. Fain, A. Gazdar, C. Gaba, H. Rothschild, D. Mandal, T. Coons, J. Lee, E. Kupert, D. Seminara, J. Minna, J. E. Bailey-Wilson, X. Wu, M. R. Spitz, T. Eisen, R. S. Houlston, C. I. Amos, M. W. Anderson, and M. You. Familial aggregation of common sequence variants on 15q24–25.1 in lung cancer. J Natl Cancer Inst. 100(18):1326–1330 (2008). source
- Not checked yetcites [103] P. Liu, H. G. Vikis, D. Wang, Y. Lu, Y. Wang, A. G. Schwartz, S. M. Pinney, P. Yang, M. De Andrade, G. M. Petersen, J. S. Wiest, P. R. Fain, A. Gazdar, C. Gaba, H. Rothschild, D. Mandal, T. Coons, J. Lee, E. Kupert, D. Seminara, J. Minna, J. E. Bailey-Wilson, X. Wu, M. R. Spitz, T. Eisen, R. S. Houlston, C. I. Amos, M. W. Anderson, and M. You. Familial aggregation of common sequence variants on 15q24–25.1 in lung cancer. J Natl Cancer Inst. 100:1326–1330 (2008). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“acid trapping does cause massive desensitization of receptors in the exocytic pathway”
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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- The authors state this as an assumption: The assembly and function of receptors within the secretory pathway is approximately normal.
None of the sources cited for this claim have been checked yet.
In the paper
“This association has been replicated either directly or using highly correlated SNPs by several groups (92–97).”
What the sources say
- Not checked yetcites [92] W. Berrettini, X. Yuan, F. Tozzi, K. Song, C. Francks, H. Chilcoat, D. Waterworth, P. Muglia, and V. Mooser. α5/α3 nicotinic receptor subunit alleles increase risk for heavy smoking. Mol Psychiatry. 13:368–373 (2008). source
- Not checked yetcites [93] L. J. Bierut, J. A. Stitzel, J. C. Wang, A. L. Hinrichs, R. A. Grucza, X. Xuei, N. L. Saccone, S. F. Saccone, S. Bertelsen, L. Fox, W. J. Horton, N. Breslau, J. Budde, C. R. Cloninger, D. M. Dick, T. Foroud, D. Hatsukami, V. Hesselbrock, E. O. Johnson, J. Kramer, S. Kuperman, P. A. Madden, K. Mayo, J. Nurnberger Jr., O. Pomerleau, B. Porjesz, O. Reyes, M. Schuckit, G. Swan, J. A. Tischfield, H. J. Edenberg, J. P. Rice, and A. M. Goate. Variants in nicotinic receptors and risk for nicotine dependence. Am J Psychiatry. 165:1163–1171 (2008). source
- Not checked yetcites [94] R. Sherva, K. Wilhelmsen, C. S. Pomerleau, S. A. Chasse, J. P. Rice, S. M. Snedecor, L. J. Bierut, R. J. Neuman, and O. F. Pomerleau. Association of a single nucleotide polymorphism in neuronal acetylcholine receptor subunit α5 (CHRNA5) with smoking status and with ‘pleasurable buzz’ during early experimentation with smoking. Addiction. 103:1544–1552 (2008). source
- Not checked yetcites [95] V. Stevens, L. Bierut, J. Talbot, W. Jc, J. Sun, A. Hinrichs, M. Thun, A. Goate, and E. Calle. Nicotinic Receptor Gene Variants Influence Susceptibility to Heavy Smoking. Cancer Epidemiol Biomarkers Prev. 17(12):3517–3525 (2008). source
- Not checked yetcites [96] T. E. Thorgeirsson, F. Geller, P. Sulem, T. Rafnar, A. Wiste, K. P. Magnusson, A. Manolescu, G. Thorleifsson, H. Stefansson, A. Ingason, S. N. Stacey, J. T. Bergthorsson, S. Thorlacius, J. Gudmundsson, T. Jonsson, M. Jakobsdottir, J. Saemundsdottir, O. Olafsdottir, L. J. Gudmundsson, G. Bjornsdottir, K. Kristjansson, H. Skuladottir, H. J. Isaksson, T. Gudbjartsson, G. T. Jones, T. Mueller, A. Gottsater, A. Flex, K. K. Aben, F. De Vegt, P. F. Mulders, D. Isla, M. J. Vidal, L. Asin, B. Saez, L. Murillo, T. Blondal, H. Kolbeinsson, J. G. Stefansson, I. Hansdottir, V. Runarsdottir, R. Pola, B. Lin source
- Not checked yetcites [97] R.A. Grucza, J. C. Wang, J. A. Stitzel, A. L. Hinrichs, S. F. Saccone, N. L. Saccone, K. K. Bucholz, C. R. Cloninger, R. J. Neuman, J. P. Budde, L. Fox, S. Bertelsen, J. Kramer, V. Hesselbrock, J. Tischfield, J. I. Nurnberger Jr., L. Almasy, B. Porjesz, S. Kuperman, M. A. Schuckit, H. J. Edenberg, J. P. Rice, A. M. Goate, and L. J. Bierut. A risk allele for nicotine dependence in CHRNA5 is a protective allele for cocaine dependence. Biol Psychiatry. 64:922–929 (2008). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Therefore, PET studies that interpret A-85380 binding may report receptor saturation by nicotine in intracellular as well as surface membrane compartments.”
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: 2-[F18]fluoro-A-85380 binds well to α4β2* and α6* nAChRs.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Therefore the so-called “acid-trapping” mechanism described here is not likely to amplify the pharmacological chaperoning effect of nicotine.”
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: The first steps in assembly and synthesis of nAChRs occur in the endoplasmic reticulum, which is roughly neutral.
None of the sources cited for this claim have been checked yet.
In the paper
“Reports that surprisingly low concentrations of nicotine saturate α4β2 receptors, and for surprisingly long periods, may partially measure the effects of much higher nicotine concentrations at receptors in such organelles (80,81).”
What the sources say
- Not checked yetcites [80] A. L. Brody, M. A. Mandelkern, E. D. London, R. E. Olmstead, J. Farahi, D. Scheibal, J. Jou, V. Allen, E. Tiongson, S. I. Chefer, A. O. Koren, and A. G. Mukhin. Cigarette smoking saturates brain α4β2 nicotinic acetylcholine receptors. Arch Gen Psychiatry. 63:907–915 (2006). source
- Not checked yetcites [81] A. L. Brody, M. A. Mandelkern, M. R. Costello, A. L. Abrams, D. Scheibal, J. Farahi, E. D. London, R. E. Olmstead, J. E. Rose, and A. G. Mukhin. Brain nicotinic acetylcholine receptor occupancy: effect of smoking a denicotinized cigarette. Int J Neuropsychopharmacol. 18:1–12 (2008). source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“although most proteostasis diseases arise from insufficient chaperoning, nicotine addiction would be a disease of excess chaperoning”
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“this mechanism for upregulation must be considered as an adjunct to SePhaChARNS”
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“This second association with nicotine dependence has been replicated in additional studies using the same SNP or a highly correlated SNP (92,95,96,98).”
What the sources say
- Not checked yetcites [92] W. Berrettini, X. Yuan, F. Tozzi, K. Song, C. Francks, H. Chilcoat, D. Waterworth, P. Muglia, and V. Mooser. α5/α3 nicotinic receptor subunit alleles increase risk for heavy smoking. Mol Psychiatry. 13:368–373 (2008). source
- Not checked yetcites [95] V. Stevens, L. Bierut, J. Talbot, W. Jc, J. Sun, A. Hinrichs, M. Thun, A. Goate, and E. Calle. Nicotinic Receptor Gene Variants Influence Susceptibility to Heavy Smoking. Cancer Epidemiol Biomarkers Prev. 17(12):3517–3525 (2008). source
- Not checked yetcites [96] T. E. Thorgeirsson, F. Geller, P. Sulem, T. Rafnar, A. Wiste, K. P. Magnusson, A. Manolescu, G. Thorleifsson, H. Stefansson, A. Ingason, S. N. Stacey, J. T. Bergthorsson, S. Thorlacius, J. Gudmundsson, T. Jonsson, M. Jakobsdottir, J. Saemundsdottir, O. Olafsdottir, L. J. Gudmundsson, G. Bjornsdottir, K. Kristjansson, H. Skuladottir, H. J. Isaksson, T. Gudbjartsson, G. T. Jones, T. Mueller, A. Gottsater, A. Flex, K. K. Aben, F. De Vegt, P. F. Mulders, D. Isla, M. J. Vidal, L. Asin, B. Saez, L. Murillo, T. Blondal, H. Kolbeinsson, J. G. Stefansson, I. Hansdottir, V. Runarsdottir, R. Pola, B. Lin source
- Not checked yetcites [98] R. B. Weiss, T. B. Baker, D. S. Cannon, A. Von Niederhausern, D. M. Dunn, N. Matsunami, N. A. Singh, L. Baird, H. Coon, W. M. Mcmahon, M. E. Piper, M. C. Fiore, M. B. Scholand, J. E. Connett, R. E. Kanner, L. C. Gahring, S. W. Rogers, J. R. Hoidal, and M. F. Leppert. A candidate gene approach identifies the CHRNA5-A3-B4 region as a risk factor for age-dependent nicotine addiction. PLoS Genet. 4:e1000125 (2008). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“During prolonged exposure to nicotine, there is deceased receptor degradation (presumably via endocytosis), and this mechanism for upregulation must be considered as an adjunct to SePhaChARNS (8,39,66,87).”
What the sources say
- Not checked yetcites [8] D. C. Perry, M. I. Davila-Garcia, C. A. Stockmeier, and K. J. Kellar. Increased nicotinic receptors in brains from smokers: membrane binding and autoradiography studies. J Pharmacol Exp Ther. 289:1545–1552 (1999). source
- Not checked yetcites [39] A. Kuryatov, J. Luo, J. Cooper, and J. Lindstrom. Nicotine acts as a pharmacological chaperone to up-regulate human α4β2 acetylcholine receptors. Mol Pharmacol. 68:1839–1851 (2005). source
- Not checked yetcites [66] X. Peng, V. Gerzanich, R. Anand, P. J. Whiting, and J. Lindstrom. Nicotine-induced increase in neuronal nicotinic receptors results from a decrease in the rate of receptor turnover. Mol Pharmacol. 46:523–530 (1994). source
- Not checked yetcites [87] F. Wang, M. E. Nelson, A. Kuryatov, F. Olale, J. Cooper, K. Keyser, and J. Lindstrom. Chronic nicotine treatment up-regulates human α3β2 but not α3β4 acetylcholine receptors stably transfected in human embryonic kidney cells. J Biol Chem. 273:28721–28732 (1998). source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“First, SePhaChARNS does not explicitly depend on direct phosphorylation (86) or other covalent modification of the nAChR.”
What the sources say
- Not checked yetcites [86] V. V. Pollock, T. Pastoor, C. Katnik, J. Cuevas, and L. Wecker. Cyclic AMP-dependent protein kinase A and protein kinase C phosphorylate α4β2 nicotinic receptor subunits at distinct stages of receptor formation and maturation. Neuroscience. (2009) (in press). source
plain- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“it does not strongly affect pharmacological chaperoning within the ER”
plain- Asserted: passes — The authors put it forward as true.
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- Based: unclear — It is unclear why the paper says it holds.
In the paper
“It is a key concept that proteostasis pathways vary among cell types, in accord with the “selective” aspect of SePhaChARNS (82).”
What the sources say
- Not checked yetcites [82] W. E. Balch, R. I. Morimoto, A. Dillin, and J. W. Kelly. Adapting proteostasis for disease intervention. Science. 319:916–919 (2008). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“These concepts’ special relevance to nAChR is summarized by Wiseman et al.’s explanation that large, slow-folding, multimembrane-spanning proteins are especially sensitive to the kinetic constraints imposed by proteostasis machinery (84).”
What the sources say
- Not checked yetcites [84] R. L. Wiseman, E. T. Powers, J. N. Buxbaum, J. W. Kelly, and W. E. Balch. An adaptable standard for protein export from the endoplasmic reticulum. Cell. 131:809–821 (2007). source
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Despite these arguments against signal transduction mechanisms evoked by Ca2+ influx through α4β2 nAChRs, Ca2+ influx is likely to play an important role in sequelae to activation of the α7 nAChR, which is highly Ca2+ permeable.”
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“The competitive antagonist DHβE also induces functional upregulation, but at higher concentrations consistent with the limited number of states available to an antagonist (48).”
What the sources say
- Not checked yetcites [48] R. Nashmi, and H. Lester. Cell autonomy, receptor autonomy, and thermodynamics in nicotine receptor up-regulation. Biochem Pharmacol. 74:1145–1154 (2007). source
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“and may accumulate, like nicotine itself, in acidic organelles”
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The SePhaChARNS mechanism depends strongly on the subunit repertoire because the subunit composition presumably controls the affinity for nicotine, the extent of interaction with the ERAD machinery, the extent to which desensitization makes many additional states available, and the extent and stability of additional stoichiometries.”
boosteddirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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- The authors state this as an assumption: Subunit composition controls the affinity for nicotine, the extent of interaction with the ERAD machinery, the extent to which desensitization makes additional states available, and the extent and stability of additional stoichiometries.
In the paper
“Expression studies have demonstrated that CHRNA5 mRNA levels show high interindividual variability in both frontal cortex and lymphocytes (99).”
What the sources say
- Not checked yetcites [99] J. Wang, R. Grucza, C. Cruchaga, A. Hinrichs, S. Bertelsen, J. Budde, L. Fox, E. Goldstein, O. Reyes, N. Saccone, S. Saccone, X. Xuei, K. Bucholz, S. Kuperman, J. Nurnberger Jr, J. Rice, M. Schuckit, J. Tischfield, V. Hesselbrock, B. Porjesz, H. Edenberg, L. Bierut, and A. Goate. Genetic variation in the CHRNA5 gene affects mRNA levels and is associated with risk for alcohol dependence. Mol Psychiatry. 18414406:(2008). source
boosted- Asserted: passes — The authors put it forward as true.
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In the paper
“Indeed, lynx1 KO mice display decreased ACh EC50 values, closer to EC50 values of the receptor expressed in oocytes alone (116).”
What the sources say
- Not checked yetcites [116] J. M. Miwa, T. R. Stevens, S. L. King, B. J. Caldarone, I. Ibanez-Tallon, C. Xiao, R. M. Fitzsimonds, C. Pavlides, H. A. Lester, M. R. Picciotto, and N. Heintz. The prototoxin lynx1 acts on nicotinic acetylcholine receptors to balance neuronal activity and survival in vivo. Neuron. 51:587–600 (2006). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The most important implication of the SePhaChARNS hypothesis is that the medically relevant manipulations of α4β2* nAChRs take place in the ER, not at the surface membrane.”
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“In peripheral ganglia such as the superior cervical ganglion, it is probably found exclusively in some, but not all, α3β4* receptors (107).”
What the sources say
- Not checked yetcites [107] D. Mao, R. P. Yasuda, H. Fan, B. B. Wolfe, and K. J. Kellar. Heterogeneity of nicotinic cholinergic receptors in rat superior cervical and nodose Ganglia. Mol Pharmacol. 70:1693–1699 (2006). source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This review shows that nicotinic drugs are expected to be effective pharmacological chaperones by acting in the ER.”
hedgeddirect- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
In the paper
“The dose–response relations of nAChR-lynx complexes agree better with in vivo agonist responses than with nAChRs expressed alone in vitro (115).”
What the sources say
- Not checked yetcites [115] M. W. Quick, and R. A. Lester. Desensitization of neuronal nicotinic receptors. J Neurobiol. 53:457–478 (2002). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Recent data indicate that the α5 subunit modifies upregulation of α4β2* receptors (112) and Lindstrom speculates that the effect proceeds at the level of chaperoning (113).”
What the sources say
- Not checked yetcites [112] D. Mao, D. C. Perry, R. P. Yasuda, B. B. Wolfe, and K. J. Kellar. The α4β2α5 nicotinic cholinergic receptor in rat brain is resistant to up-regulation by nicotine in vivo. J Neurochem. 104:446–456 (2007). source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“In rodent brain which has been extensively studied, it is found in some, but not all, α4β2* receptors in cortex, thalamus, striatum, hippocampus, medial habenula, olfactory tubercle, hypothalamus, and midbrain (dopaminergic neurons only) (105,106).”
What the sources say
- Not checked yetcites [105] R. W. Brown, A. C. Collins, J. M. Lindstrom, and P. Whiteaker. Nicotinic α5 subunit deletion locally reduces high-affinity agonist activation without altering nicotinic receptor numbers. J Neurochem. 103:204–215 (2007). source
- Not checked yetcites [106] L. Azam, Y. Chen, and F. M. Leslie. Developmental regulation of nicotinic acetylcholine receptors within midbrain dopamine neurons. Neuroscience. 144:1347–1360 (2007). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Lynx, a glycophosphoinositide-linked (GPI-linked) protein, is topologically well placed to bind in such fashion.”
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We conclude that lynx1 modulates nAChR function in vivo.”
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, this accessory subunit may partially govern the cellular or subcellular selectivity in the SePhaChARNS hypothesis.”
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These data indicate that lynx molecules can account for much of the differences between in vivo and in vitro nAChR functioning.”
hedgeddirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“We also conclude that lynx1 plays a critical role in maintaining a balance between the beneficial effects of short-term nAChR activation (117) and the potentially devastating degenerative excitotoxic effects of chronic over-activation of nAChRs (118,119).”
What the sources say
- Not checked yetcites [117] E. D. Levin. Nicotinic receptor subtypes and cognitive function. J Neurobiol. 53:633–640 (2002). source
- Not checked yetcites [118] A. Orr-Urtreger, R. S. Broide, M. R. Kasten, H. Dang, J. A. Dani, A. L. Beaudet, and J. W. Patrick. Mice homozygous for the L250T mutation in the α7 nicotinic acetylcholine receptor show increased neuronal apoptosis and die within 1 day of birth. J Neurochem. 74:2154–2166 (2000). source
- Not checked yetcites [119] C. Labarca, J. Schwarz, P. Deshpande, S. Schwarz, M. W. Nowak, C. Fonck, R. Nashmi, P. Kofuji, H. Dang, W. Shi, M. Fidan, B. S. Khakh, Z. Chen, B. J. Bowers, J. Boulter, J. M. Wehner, and H. A. Lester. Point mutant mice with hypersensitive α4 nicotinic receptors show dopaminergic deficits and increased anxiety. Proc Natl Acad Sci U S A. 98:2786–2791 (2001). source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- It may state two separate claims as one. 41
- Probably not a substantial claim. 27
Every source the paper cites for this claim was checked and supports it.
In the paper
“Upregulation occurs in the GABAergic neurons of the ventral tegmental area (VTA), but not in the somata of the dopaminergic neurons which are postsynaptic targets of, and inhibited by, the GABAergic neurons.”
What the sources say
- Supportedcites [5] R. Nashmi, C. Xiao, P. Deshpande, S. Mckinney, S. R. Grady, P. Whiteaker, Q. Huang, T. Mcclure-Begley, J. M. Lindstrom, C. Labarca, A. C. Collins, M. J. Marks, and H. A. Lester. Chronic nicotine cell specifically upregulates functional α4* nicotinic receptors: basis for both tolerance in midbrain and enhanced long-term potentiation in perforant path. J Neurosci. 27:8202–8218 (2007). source
The Figure 4 caption (page unavailable) reports increased α4YFP fluorescence in VTA GABAergic neurons after chronic nicotine, with very little change in VTA dopaminergic neurons. The Discussion (page unavailable) says the dopaminergic measurements emphasize cell bodies and describes GABAergic inhibition of dopaminergic target neurons. (LLM, conf=0.92)
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“In consequence, SNc DA neurons from chronic nicotine-treated mice have a lower baseline firing rate and a lower incidence of burst firing.”
What the sources say
- Partly supportedcites [5] R. Nashmi, C. Xiao, P. Deshpande, S. Mckinney, S. R. Grady, P. Whiteaker, Q. Huang, T. Mcclure-Begley, J. M. Lindstrom, C. Labarca, A. C. Collins, M. J. Marks, and H. A. Lester. Chronic nicotine cell specifically upregulates functional α4* nicotinic receptors: basis for both tolerance in midbrain and enhanced long-term potentiation in perforant path. J Neurosci. 27:8202–8218 (2007). sourceExperimental — accuracy not yet measured
The section on firing frequency reports significantly lower baseline firing rates in SNC dopaminergic neurons from chronic nicotine-treated mice than in saline-treated mice. In “Possible mechanisms in substantia nigra” (page unavailable), decreased burst firing is proposed as a possible consequence in an intact animal, not reported as a measured lower incidence in the treated mice. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Experiments with cultures from α4-hypersensitive mice also show that upregulation occurs (a) at chronic nicotine concentrations that activate only α4* receptors, (b) in homotypic GABAergic cultures lacking their typical presynaptic partners, and (c) when tested with ACh concentrations that activate only the α4* receptors (48,49).”
What the sources say
- Supportedcites [48] R. Nashmi, and H. Lester. Cell autonomy, receptor autonomy, and thermodynamics in nicotine receptor up-regulation. Biochem Pharmacol. 74:1145–1154 (2007). source
The Discussion states all three points: up-regulation at 10 nM nicotine that activated only α4* receptors, in homotypic GABAergic cultures lacking their typical presynaptic partners, and when tested with ACh concentrations that activated only α4* receptors. The Results also describe the selective nicotine exposure and low-dose ACh test. (LLM, conf=0.94)
- Not checked yetcites [49] A. Tapper, S. Mckinney, R. Nashmi, J. Schwarz, P. Deshpande, C. Labarca, P. Whiteaker, A. Collins, and H. Lester. Nicotine activation of α4* receptors: sufficient for reward, tolerance and sensitization. Science. 306:1029–1032 (2004). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
In the paper
“As a result, chronic nicotine increases both the baseline firing rate and the excitatory effect of nicotine in GABAergic neurons, while decreasing baseline firing rate and attenuating the excitatory effect of nicotine in dopaminergic neurons (5) (C. Xiao and H. Lester, unpublished).”
What the sources say
- Not checked yetcites [5] R. Nashmi, C. Xiao, P. Deshpande, S. Mckinney, S. R. Grady, P. Whiteaker, Q. Huang, T. Mcclure-Begley, J. M. Lindstrom, C. Labarca, A. C. Collins, M. J. Marks, and H. A. Lester. Chronic nicotine cell specifically upregulates functional α4* nicotinic receptors: basis for both tolerance in midbrain and enhanced long-term potentiation in perforant path. J Neurosci. 27:8202–8218 (2007). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“However, no such augmentation was observed when either the chronic nicotine exposure was omitted, or the acute exposure during the tetanus was omitted, or both (5).”
What the sources say
- Not checked yetcites [5] R. Nashmi, C. Xiao, P. Deshpande, S. Mckinney, S. R. Grady, P. Whiteaker, Q. Huang, T. Mcclure-Begley, J. M. Lindstrom, C. Labarca, A. C. Collins, M. J. Marks, and H. A. Lester. Chronic nicotine cell specifically upregulates functional α4* nicotinic receptors: basis for both tolerance in midbrain and enhanced long-term potentiation in perforant path. J Neurosci. 27:8202–8218 (2007). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Chronic exposure to nicotine produces new functional α4β2* receptors on all substantia nigra pars reticulata (SNr) GABAergic neurons, but not on their postsynaptic targets, the DA neurons of substantia nigra pars compacta (SNc).”
What the sources say
- Not checked yetcites [5] R. Nashmi, C. Xiao, P. Deshpande, S. Mckinney, S. R. Grady, P. Whiteaker, Q. Huang, T. Mcclure-Begley, J. M. Lindstrom, C. Labarca, A. C. Collins, M. J. Marks, and H. A. Lester. Chronic nicotine cell specifically upregulates functional α4* nicotinic receptors: basis for both tolerance in midbrain and enhanced long-term potentiation in perforant path. J Neurosci. 27:8202–8218 (2007). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“and that increases in inhibition could provide an explanation for tolerance to the chronic effects of nicotine (5).”
What the sources say
- Not checked yetcites [5] R. Nashmi, C. Xiao, P. Deshpande, S. Mckinney, S. R. Grady, P. Whiteaker, Q. Huang, T. Mcclure-Begley, J. M. Lindstrom, C. Labarca, A. C. Collins, M. J. Marks, and H. A. Lester. Chronic nicotine cell specifically upregulates functional α4* nicotinic receptors: basis for both tolerance in midbrain and enhanced long-term potentiation in perforant path. J Neurosci. 27:8202–8218 (2007). source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
In the paper
“We now know that α4β2* receptors (* = IUPHAR nomenclature, “other subunits may be present”) are selectively upregulated (a partial reason for the initial “Se” in SePhaChARNS) but that other subtypes are also upregulated (3);”
What the sources say
- Not checked yetcites [3] H. N. Nguyen, B. A. Rasmussen, and D. C. Perry. Subtype-selective up-regulation by chronic nicotine of high-affinity nicotinic receptors in rat brain demonstrated by receptor autoradiography. J Pharmacol Exp Ther. 307:1090–1097 (2003). source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Nicotine makes neither interaction with the muscle receptor (45,46).”
What the sources say
- Not checked yetcites [45] D. L. Beene, G. S. Brandt, W. Zhong, N. M. Zacharias, H. A. Lester, and D. A. Dougherty. Cation-π interactions in ligand recognition by serotonergic (5-HT3A) and nicotinic acetylcholine receptors: the anomalous binding properties of nicotine. Biochemistry. 41:10262–10269 (2002). source
- Not checked yetcites [46] A. L. Cashin, E. J. Petersson, H. A. Lester, and D. A. Dougherty. Using physical chemistry to differentiate nicotinic from cholinergic agonists at the nicotinic acetylcholine receptor. J Am Chem Soc. 127:350–356 (2005). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This implies that nicotine can also enter the endoplasmic reticulum and other organelles.”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“If ACh survived for several hours near neurons (which is not the case), it too would produce SePhaChARNS.”
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“However, the in vitro effect of nicotine brings partial rationalization to its in vivo effect and suggests new clues about the pathophysiology.”
What the sources say
- Not checked yetcites C. Son, F. Moss, B. N. Cohen, H. A. Lester, submitted
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Quaternary amines with substantial hydrophobic substituents also display detectable membrane permeability; this is revealed in the literature on blockers of voltage-gated ion channels.”
What the sources say
- Not checked yetcites [40] C. M. Armstrong. Interaction of tetraethylamonium ion derivatives with the potassium channels of giant axons. J. Gen. Physiol. 58:413–437 (1971). source
- Not checked yetcites [41] M. Taglialatela, A. M. Vandongen, J. A. Drewe, R. H. Joho, A. M. Brown, and G. E. Kirsch. Patterns of internal and external tetraethylammonium block in four homologous K+ channels. Mol Pharmacol. 40:299–307 (1991). source
- Not checked yetcites [42] G. K. Wang, C. Quan, M. Vladimirov, W. M. Mok, and J. G. Thalhammer. Quaternary ammonium derivative of lidocaine as a long-acting local anesthetic. Anesthesiology. 83:1293–1301 (1995). source
- Not checked yetcites [43] T. K. Lim, B. A. Macleod, C. R. Ries, and S. K. Schwarz. The quaternary lidocaine derivative, QX-314, produces long-lasting local anesthesia in animal models in vivo. Anesthesiology. 107:305–311 (2007). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“These effects on dopaminergic terminals extend and confirm other reports that chronic nicotine increases nicotine-induced dopamine release (25,26) and upregulates receptors in striatum (5).”
What the sources say
- Not checked yetcites [25] D. L. Marshall, P. H. Redfern, and S. Wonnacott. Presynaptic nicotinic modulation of dopamine release in the three ascending pathways studied by in vivo microdialysis: comparison of naive and chronic nicotine-treated rats. J Neurochem. 68:1511–1519 (1997). source
- Not checked yetcites [26] N. P. Visanji, S. N. Mitchell, M. J. O'neill, and S. Duty. Chronic pre-treatment with nicotine enhances nicotine-evoked striatal dopamine release and α6 and β3 nicotinic acetylcholine receptor subunit mRNA in the substantia nigra pars compacta of the rat. Neuropharmacology. 50:36–46 (2006). source
- Not checked yetcites [5] R. Nashmi, C. Xiao, P. Deshpande, S. Mckinney, S. R. Grady, P. Whiteaker, Q. Huang, T. Mcclure-Begley, J. M. Lindstrom, C. Labarca, A. C. Collins, M. J. Marks, and H. A. Lester. Chronic nicotine cell specifically upregulates functional α4* nicotinic receptors: basis for both tolerance in midbrain and enhanced long-term potentiation in perforant path. J Neurosci. 27:8202–8218 (2007). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Nicotine is metabolized only by liver enzymes and disappears from blood with a half-life of ~120 min (35).”
What the sources say
- Not checked yetcites [35] S. G. Matta, D. J. Balfour, N. L. Benowitz, R. T. Boyd, J. J. Buccafusco, A. R. Caggiula, C. R. Craig, A. C. Collins, M. I. Damaj, E. C. Donny, P. S. Gardiner, S. R. Grady, U. Heberlein, S. S. Leonard, E. D. Levin, R. J. Lukas, A. Markou, M. J. Marks, S. E. Mccallum, N. Parameswaran, K. A. Perkins, M. R. Picciotto, M. Quik, J. E. Rose, A. Rothenfluh, W. R. Schafer, I. P. Stolerman, R. F. Tyndale, J. M. Wehner, and J. M. Zirger. Guidelines on nicotine dose selection for in vivo research. Psychopharmacology (Berl). 190:269–319 (2007). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“The EC50 for nicotine at (α4)2(β2)3 neuronal receptors is ~1 μM; at (α1)2β1γδ muscle receptors, ~ 400 μM.”
What the sources say
- Not checked yetcites [44] X. X. Xiu, N. Puskar, J. Shanata, H. A. Lester, and D. A. Dougherty. Nicotine binding to brain receptors requires a strong cation-π interaction Nature. (in press) (2009). source
- Not checked yetcites [45] D. L. Beene, G. S. Brandt, W. Zhong, N. M. Zacharias, H. A. Lester, and D. A. Dougherty. Cation-π interactions in ligand recognition by serotonergic (5-HT3A) and nicotinic acetylcholine receptors: the anomalous binding properties of nicotine. Biochemistry. 41:10262–10269 (2002). source
- Not checked yetcites [46] A. L. Cashin, E. J. Petersson, H. A. Lester, and D. A. Dougherty. Using physical chemistry to differentiate nicotinic from cholinergic agonists at the nicotinic acetylcholine receptor. J Am Chem Soc. 127:350–356 (2005). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Nicotine is quite effective as a smoked drug because it permeates at least six membranes, in the lungs and capillary walls, within a few seconds of inhalation.”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: unclear — It is unclear why the paper says it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, because agonists open the channel, they allow access to many more conformational states than do antagonists; and if these new states have high affinity, then SePhaChARNS is strengthened, whether or not the new conformational states have open channels.”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Unsurprisingly, hexamethonium, mecamylamine, or decamethonium by themselves do not produce appreciable up-regulation (54,65).”
What the sources say
- Not checked yetcites [54] T. Darsow, T. K. Booker, J. C. Pina-Crespo, and S. F. Heinemann. Exocytic trafficking is required for nicotine-induced up-regulation of α4β2 nicotinic acetylcholine receptors. J Biol Chem. 280:18311–18320 (2005). source
- Not checked yetcites [65] P. Whiteaker, C. G. Sharples, and S. Wonnacott. Agonist-induced up-regulation of α4β2 nicotinic acetylcholine receptors in M10 cells: pharmacological and spatial definition. Mol Pharmacol. 53:950–962 (1998). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“(2) It must be present at concentrations greater than its equilibrium dissociation constant for the nAChR subtype (including the particular stoichiometry) that it will chaperone.”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“In fact, neither hexamethonium (61) nor chlorisondamine (62), two well-studied channel blockers at nAChRs, are foot-in-the door blockers at high-sensitivity α4β2 receptors;”
What the sources say
- Not checked yetcites [61] P. Charnet, C. Labarca, B. N. Cohen, N. Davidson, H. A. Lester, and G. Pilar. Pharmacological and kinetic properties of α4β2 neuronal nicotinic acetylcholine receptors expressed in Xenopus oocytes. J Physiol. 450:375–394 (1992). source
- Not checked yetcites [62] C. A. Briggs, E. J. Gubbins, M. J. Marks, C. B. Putman, R. Thimmapaya, M. D. Meyer, and C. S. Surowy. Untranslated region-dependent exclusive expression of high-sensitivity subforms of α4β2 and α3β2 nicotinic acetylcholine receptors. Mol Pharmacol. 70:227–240 (2006). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These differences show how nicotine can activate and upregulate (α4)2(β2)3 receptors but have minimal effect on muscle receptors.”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“In the absence of energy input, any reversible chemical interaction eventually reaches its state of lowest free energy, if the kinetic barriers are low enough to allow access to these states on the time scale of nicotine’s presence.”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“The upregulated receptors are apparently shifted toward the high nicotine affinity, high-sensitivity (α4)2(β2)3 stoichiometry, at the expense of the lower-sensitivity (α4)3(β2)2 stoichiometry.”
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“(3) It should bind at one or more subunit interfaces in the pentameric complex, so that it can stabilize the assembled rather than unassembled receptor.”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Several studies suggest that the two forms differ in subunit composition: the high- and low-sensitivity forms would consist of the (α4)2(β2)3 and (α4)3(β2)2 pentamers, respectively (74–76).”
What the sources say
- Not checked yetcites [74] R. Zwart, and H. P. Vijverberg. Four pharmacologically distinct subtypes of α4β2 nicotinic acetylcholine receptor expressed in Xenopus laevis oocytes. Mol Pharmacol. 54:1124–1131 (1998). source
- Not checked yetcites [75] Y. Zhou, M. E. Nelson, A. Kuryatov, C. Choi, J. Cooper, and J. Lindstrom. Human α4β2 acetylcholine receptors formed from linked subunits. J Neurosci. 23:9004–9015 (2003). source
- Not checked yetcites [76] M. E. Nelson, A. Kuryatov, C. H. Choi, Y. Zhou, and J. Lindstrom. Alternate stoichiometries of α4β2 nicotinic acetylcholine receptors. Mol Pharmacol. 63:332–341 (2003). source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These observations agree well with the SePhaChARNS mechanism, which makes no explicit statements about agonists vs antagonists.”
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Descriptions that may be essentially equivalent to SePhaChARNS are the statements that nicotine acts as a “maturational enhancer” or a “novel slow stabilizer” for α4β2* receptors (39,50–52).”
What the sources say
- Not checked yetcites [39] A. Kuryatov, J. Luo, J. Cooper, and J. Lindstrom. Nicotine acts as a pharmacological chaperone to up-regulate human α4β2 acetylcholine receptors. Mol Pharmacol. 68:1839–1851 (2005). source
- Not checked yetcites [50] J. Sallette, S. Pons, A. Devillers-Thiery, M. Soudant, L. Prado De Carvalho, J. P. Changeux, and P. J. Corringer. Nicotine upregulates its own receptors through enhanced intracellular maturation. Neuron. 46:595–607 (2005). source
- Not checked yetcites [51] P. Tumkosit, A. Kuryatov, J. Luo, and J. Lindstrom. β3 subunits promote expression and nicotine-induced up-regulation of human nicotinic α6* nicotinic acetylcholine receptors expressed in transfected cell lines. Mol Pharmacol. 70:1358–1368 (2006). source
- Not checked yetcites [52] Y. F. Vallejo, B. Buisson, D. Bertrand, and W. N. Green. Chronic nicotine exposure upregulates nicotinic receptors by a novel mechanism. J Neurosci. 25:5563–5572 (2005). source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Mecamylamine, a frequently used nonspecific nAChR channel blocker, lacks foot-in-the-door properties at ganglionic nAChRs (64) and has not been evaluated for such properties at α4β2 receptors.”
What the sources say
- Not checked yetcites [64] A. M. Gurney, and H. P. Rang. The channel-blocking action of methonium compounds on rat submandibular ganglion cells. Br. J. Pharmacol. 82:623–642 (1984). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Selective nicotine binding to α4* nAChRs is sufficient for α4* receptor upregulation when α4* receptors are heterologously expressed in mammalian cell lines, as well as in almost pure cultures of GABAergic ventral midbrain neurons (48).”
What the sources say
- Not checked yetcites [48] R. Nashmi, and H. Lester. Cell autonomy, receptor autonomy, and thermodynamics in nicotine receptor up-regulation. Biochem Pharmacol. 74:1145–1154 (2007). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Here are the requirements for an effective pharmacological chaperone for nAChRs. (1) The drug must penetrate to the lumen of the endoplasmic reticulum.”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds.
In the paper
“Upregulation induced in animal models and transfected cells by chronic nicotine is certainly not transcriptional and is probably post-translational (47).”
What the sources say
- Not checked yetcites [47] J. R. Pauly, M. J. Marks, S. F. Robinson, J. L. Van De Kamp, and A. C. Collins. Chronic nicotine and mecamylamine treatment increase brain nicotinic receptor binding without changing α4 or β2 mRNA levels. J Pharmacol Exp Ther. 278:361–369 (1996). source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Nicotine accumulates within cells, so that the apparent “intracellular volume” occupied by nicotine is six- to eightfold greater than the total intracellular volume measured, for instance, by inulin exclusion.”
What the sources say
- Not checked yetcites [77] J. W. Putney Jr., and J. F. Borzelleca. On the mechanisms of [14C]nicotine distribution in rat submaxillary gland in vitro. J Pharmacol Exp Ther. 178:180–191 (1971). source
- Not checked yetcites [78] A. Roos, and W. F. Boron. Intracellular pH. Physiol. Rev. 61:296–434 (1981). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“Exocytosis is required for upregulation, presumably because exocytosis is downstream from SePhaChARNS (53).”
What the sources say
- Not checked yetcites [53] J. Xu, Y. Zhu, and S. F. Heinemann. Identification of sequence motifs that target neuronal nicotinic receptors to dendrites and axons. J Neurosci. 26:9780–9793 (2006). source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: unclear — It is unclear why the paper says it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“A pH of 6.5, roughly 0.5 pH unit lower than the cytoplasmic pH, implies a concentration of nicotine threefold higher in the organelle than in the cytoplasm; at pH 5.5, the ratio is 30.”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Human α4 harboring a Ser247Phe mutation (at the M2 6′ position) renders the channel nonfunctional in HEK tsA201 cells, and yet chronic nicotine induces robust upregulation of the receptor in this clonal cell line (39).”
What the sources say
- Not checked yetcites [39] A. Kuryatov, J. Luo, J. Cooper, and J. Lindstrom. Nicotine acts as a pharmacological chaperone to up-regulate human α4β2 acetylcholine receptors. Mol Pharmacol. 68:1839–1851 (2005). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“The most thoroughly investigated and replicated finding to date is the association with rs16969968, in CHRNA5 (91).”
What the sources say
- Not checked yetcites [91] S. F. Saccone, A. L. Hinrichs, N. L. Saccone, G. A. Chase, K. Konvicka, P. A. Madden, N. Breslau, E. O. Johnson, D. Hatsukami, O. Pomerleau, G. E. Swan, A. M. Goate, J. Rutter, S. Bertelsen, L. Fox, D. Fugman, N. G. Martin, G. W. Montgomery, J. C. Wang, D. G. Ballinger, J. P. Rice, and L. J. Bierut. Cholinergic nicotinic receptor genes implicated in a nicotine dependence association study targeting 348 candidate genes with 3713 SNPs. Human Molecular Genetics. 16:36–49 (2007). source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, if their assembly and function is approximately normal, then it is a strong conclusion that, in the presence of smoked nicotine, receptors are primarily in a desensitized state before they reach the cell surface.”
boostedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- The authors state this as an assumption: The assembly and function of receptors within the secretory pathway is approximately normal.
In the paper
“In the ion channel field, one relevant example is the use of small-molecule proteostasis regulators to stabilize the misfolding-prone ΔF508 mutant of the cystic fibrosis transmembrane conductance regulator (83).”
What the sources say
- Not checked yetcites [83] Www.Clinicaltrials.Gov . [cited.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“A second signal in the CHRNA5/A3/B4 cluster is tagged by SNP rs578776; it is strongly associated with nicotine dependence and has a low correlation with rs16969968 (r2 = 0.18), indicating that it represents a statistically independent signal (90,91).”
What the sources say
- Not checked yetcites [90] L. J. Bierut, P. A. Madden, N. Breslau, E. O. Johnson, D. Hatsukami, O. F. Pomerleau, G. E. Swan, J. Rutter, S. Bertelsen, L. Fox, D. Fugman, A. M. Goate, A. L. Hinrichs, K. Konvicka, N. G. Martin, G. W. Montgomery, N. L. Saccone, S. F. Saccone, J. C. Wang, G. A. Chase, J. P. Rice, and D. G. Ballinger. Novel genes identified in a high-density genome wide association study for nicotine dependence. Hum Mol Genet. 16:24–35 (2007). source
- Not checked yetcites [91] S. F. Saccone, A. L. Hinrichs, N. L. Saccone, G. A. Chase, K. Konvicka, P. A. Madden, N. Breslau, E. O. Johnson, D. Hatsukami, O. Pomerleau, G. E. Swan, A. M. Goate, J. Rutter, S. Bertelsen, L. Fox, D. Fugman, N. G. Martin, G. W. Montgomery, J. C. Wang, D. G. Ballinger, J. P. Rice, and L. J. Bierut. Cholinergic nicotinic receptor genes implicated in a nicotine dependence association study targeting 348 candidate genes with 3713 SNPs. Human Molecular Genetics. 16:36–49 (2007). source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Thus, in one view, stabilization of high-affinity nicotinic receptors by chronic nicotine is a thermodynamic necessity (48).”
What the sources say
- Not checked yetcites [48] R. Nashmi, and H. Lester. Cell autonomy, receptor autonomy, and thermodynamics in nicotine receptor up-regulation. Biochem Pharmacol. 74:1145–1154 (2007). source
hedgeddirect- Asserted: fails — The authors may not put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The authors may not put it forward as true.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Second, SePhaChARNS does not explicitly include nicotine-evoked changes in endocytosis or exocytosis.”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“At present, we believe that α4β2 receptors, in the absence of additional subunits, may be more amenable to SePhaChARNS than other subtypes, for the constellation of reasons just given; but this impression may simply derive from our more complete knowledge of this subtype.”
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The noncoding mutations, such as rs578776, could affect the level of expression of the α5 protein, therefore affect the proportion of α4β2* receptors that are α4β2α5* receptors, and thus also affect chaperoning.”
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Knockout mice for the α5 subunit display a reduction in the somatic but not affective signs of nicotine withdrawal, probably arising from autonomic ganglia and other peripheral α3* nAChRs (14).”
What the sources say
- Not checked yetcites [14] K. J. Jackson, B. R. Martin, J. P. Changeux, and M. I. Damaj. Differential role of nicotinic acetylcholine receptor subunits in physical and affective nicotine withdrawal signs. J Pharmacol Exp Ther. 325:302–312 (2008). source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Lynx1KO mice demonstrate cognitive enhancements and neurological changes (116), features associated with hyperactive nAChRs, including improved learning, increased intracellular Ca2+ in response to nicotine treatment, less receptor desensitization, and heightened nicotine sensitivity.”
What the sources say
- Not checked yetcites [116] J. M. Miwa, T. R. Stevens, S. L. King, B. J. Caldarone, I. Ibanez-Tallon, C. Xiao, R. M. Fitzsimonds, C. Pavlides, H. A. Lester, M. R. Picciotto, and N. Heintz. The prototoxin lynx1 acts on nicotinic acetylcholine receptors to balance neuronal activity and survival in vivo. Neuron. 51:587–600 (2006). source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“In the presence of lynx1, α4β2 nAChRs are up to 20-fold less sensitive to ACh in a Xenopus oocyte expression system, desensitize more rapidly, and recover more slowly from desensitization (114).”
What the sources say
- Not checked yetcites [114] I. Ibanez-Tallon, J. M. Miwa, H. L. Wang, N. C. Adams, G. W. Crabtree, S. M. Sine, and N. Heintz. Novel modulation of neuronal nicotinic acetylcholine receptors by association with the endogenous prototoxin lynx1. Neuron. 33:893–903 (2002). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“SLURP1 differs from lynx1 in that SLURP1 is expressed in the periphery, not in neurons, and is not GPI anchored, but is secreted out of the cell (121,122).”
What the sources say
- Not checked yetcites [121] M. Skok, R. Grailhe, and J. P. Changeux. Nicotinic receptors regulate B lymphocyte activation and immune response. Eur J Pharmacol. 517:246–251 (2005). source
- Not checked yetcites [122] M. V. Skok, R. Grailhe, F. Agenes, and J. P. Changeux. The role of nicotinic receptors in B-lymphocyte development and activation. Life Sci. 80:2334–2336 (2007). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“For example, SLURP-1 is mutated in Mal de Meleda (120).”
What the sources say
- Not checked yetcites [120] F. Chimienti, R. C. Hogg, L. Plantard, C. Lehmann, N. Brakch, J. Fischer, M. Huber, D. Bertrand, and D. Hohl. Identification of SLURP-1 as an epidermal neuromodulator explains the clinical phenotype of Mal de Meleda. Hum Mol Genet. 12:3017–3024 (2003). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“In lung, lynx1 is co-expressed with nAChRs (125).”
What the sources say
- Not checked yetcites [125] H. S. Sekhon, P. Song, Y. Jia, J. Lindstrom, and E. R. Spindel. Expression of lynx1 in developing lung and its modulation by prenatal nicotine exposure. Cell Tissue Res. 320:287–297 (2005). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In other words, we think it is possible that a key lynx–nAChR interaction occurs during receptor biosynthesis and maturation, in addition to acute nicotine–receptor interactions at the surface membrane.”
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
In the paper
“Aging lynx1 KO mice undergo a striatal degeneration which is exacerbated by nicotine and ameliorated by crossing lynx1KO mice with those lacking α7 nAChRs, indicating that both α7 and α4β2-type nAChRs may be important targets of lynx1 genes (116).”
What the sources say
- Not checked yetcites [116] J. M. Miwa, T. R. Stevens, S. L. King, B. J. Caldarone, I. Ibanez-Tallon, C. Xiao, R. M. Fitzsimonds, C. Pavlides, H. A. Lester, M. R. Picciotto, and N. Heintz. The prototoxin lynx1 acts on nicotinic acetylcholine receptors to balance neuronal activity and survival in vivo. Neuron. 51:587–600 (2006). source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“while others report an increased risk of lung cancer even in nonsmokers, suggesting the possibility of a direct effect on lung cancer vulnerability (101,104).”
What the sources say
- Not checked yetcites [101] R. J. Hung, J. D. Mckay, V. Gaborieau, P. Boffetta, M. Hashibe, D. Zaridze, A. Mukeria, N. Szeszenia-Dabrowska, J. Lissowska, P. Rudnai, E. Fabianova, D. Mates, V. Bencko, L. Foretova, V. Janout, C. Chen, G. Goodman, J. K. Field, T. Liloglou, G. Xinarianos, A. Cassidy, J. Mclaughlin, G. Liu, S. Narod, H. E. Krokan, F. Skorpen, M. B. Elvestad, K. Hveem, L. Vatten, J. Linseisen, F. Clavel-Chapelon, P. Vineis, H. B. Bueno-De-Mesquita, E. Lund, C. Martinez, S. Bingham, T. Rasmuson, P. Hainaut, E. Riboli, W. Ahrens, S. Benhamou, P. Lagiou, D. Trichopoulos, I. Holcatova, F. Merletti, K. Kjaerheim, A source
- Not checked yetcites [104] C. I. Amos, X. Wu, P. Broderick, I. P. Gorlov, J. Gu, T. Eisen, Q. Dong, Q. Zhang, X. Gu, J. Vijayakrishnan, K. Sullivan, A. Matakidou, Y. Wang, G. Mills, K. Doheny, Y. Y. Tsai, W. V. Chen, S. Shete, M. R. Spitz, and R. S. Houlston. Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1. Nat Genet. 40:616–622 (2008). source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“It is also possible that SePhaChARNS could be manipulated by drugs that modify protein chaperones.”
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
In the paper
“some indicate that the association could be explained through an indirect effect on risk for smoking (96)”
What the sources say
- Not checked yetcites [96] T. E. Thorgeirsson, F. Geller, P. Sulem, T. Rafnar, A. Wiste, K. P. Magnusson, A. Manolescu, G. Thorleifsson, H. Stefansson, A. Ingason, S. N. Stacey, J. T. Bergthorsson, S. Thorlacius, J. Gudmundsson, T. Jonsson, M. Jakobsdottir, J. Saemundsdottir, O. Olafsdottir, L. J. Gudmundsson, G. Bjornsdottir, K. Kristjansson, H. Skuladottir, H. J. Isaksson, T. Gudbjartsson, G. T. Jones, T. Mueller, A. Gottsater, A. Flex, K. K. Aben, F. De Vegt, P. F. Mulders, D. Isla, M. J. Vidal, L. Asin, B. Saez, L. Murillo, T. Blondal, H. Kolbeinsson, J. G. Stefansson, I. Hansdottir, V. Runarsdottir, R. Pola, B. Lin source
hedgedconditional- Asserted: fails — The authors may not put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The authors may not put it forward as true. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Bronchial epithelium, squamous cell lung carcinoma, non-small-cell lung cancers, and BEP2D cells express α5 subunits (108–110); but their partner subunits and functional states are not known.”
What the sources say
- Not checked yetcites [108] A. D. Maus, E. F. Pereira, P. I. Karachunski, R. M. Horton, D. Navaneetham, K. Macklin, W. S. Cortes, E. X. Albuquerque, and B. M. Conti-Fine. Human and rodent bronchial epithelial cells express functional nicotinic acetylcholine receptors. Mol Pharmacol. 54:779–788 (1998). source
- Not checked yetcites [109] J. Arredondo, A. I. Chernyavsky, and S. A. Grando. The nicotinic receptor antagonists abolish pathobiologic effects of tobacco-derived nitrosamines on BEP2D cells. J Cancer Res Clin Oncol. 132:653–663 (2006). source
- Not checked yetcites [110] P. Song, H. S. Sekhon, X. W. Fu, M. Maier, Y. Jia, J. Duan, B. J. Proskosil, C. Gravett, J. Lindstrom, G. P. Mark, S. Saha, and E. R. Spindel. Activated cholinergic signaling provides a target in squamous cell lung carcinoma. Cancer Res. 68:4693–4700 (2008). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Other studies on α5 knockout mice show changes in both presynaptic and somatodendritic nAChR responses (111).”
What the sources say
- Not checked yetcites [111] H. Fischer, A. Orr-Urtreger, L. W. Role, and S. Huck. Selective deletion of the α5 subunit differentially affects somatic-dendritic versus axonally targeted nicotinic ACh receptors in mouse. J Physiol. 563:119–137 (2005). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The rs16969968, coding-region mutation, in the M3–M4 cytoplasmic loop, could interact with ERAD machinery to alter chaperoning.”
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“A modest and obvious extension of this idea is that lynx may bind to non-agonist interfaces, such as the α4–α4 interface in (α4)3(β2)2 receptors, or the allosterically important α4–α5 interface if the complex includes an α5 subunit (113,126).”
What the sources say
- Not checked yetcites [113] A. Kuryatov, J. Onksen, and J. Lindstrom. Roles of accessory subunits in α4β2α5 nicotinic receptors. Mol Pharmacol. 74:132–143 (2008). source
- Not checked yetcites [126] S. M. Kassam, P. M. Herman, N. M. Goodfellow, N. C. Alves, and E. K. Lambe. Developmental excitation of corticothalamic neurons by nicotinic acetylcholine receptors. J Neurosci. 28:8756–8764 (2008). source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, one may best discover drugs that affect SePhaChARNS by studying events in the ER.”
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence.
None of the sources cited for this claim have been checked yet.
In the paper
“SLURPs enhance this process (123) as well as oral and lung cancer cell proliferation (124).”
What the sources say
- Not checked yetcites [123] J. Arredondo, A. I. Chernyavsky, R. J. Webber, and S. A. Grando. Biological effects of SLURP-1 on human keratinocytes. J Invest Dermatol. 125:1236–1241 (2005). source
- Not checked yetcites [124] J. Arredondo, A. I. Chernyavsky, and S. A. Grando. SLURP-1 and -2 in normal, immortalized and malignant oral keratinocytes. Life Sci. 80:2243–2247 (2007). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Furthermore, they suggest that lynx proteins oppose some of the effects of chronic nicotine exposure, and have a desensitizing influence on nAChRs.”
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The authors state this as an assumption.
All drugs in Table I may be assumed to have pKa values between 7.4 and 8.
“All drugs in this list may be assumed to have pKa values between 7.4 and 8.”
The paper relies on this without support.
The first steps in assembly and synthesis of nAChRs occur in the endoplasmic reticulum, which is roughly neutral.
“The first steps in assembly and synthesis of nAChRs occur in the endoplasmic reticulum (ER) itself, which is roughly neutral.”
The authors state this as an assumption.
The assembly and function of receptors within the secretory pathway is approximately normal.
“if their assembly and function is approximately normal”
The authors state this as an assumption.
Surface receptors recover from desensitization within a matter of minutes after exposure to extracellular nicotine.
“Presumably, they recover from desensitization within a matter of minutes.”
The authors state this as an assumption.
Subunit composition controls the affinity for nicotine, the extent of interaction with the ERAD machinery, the extent to which desensitization makes additional states available, and the extent and stability of additional stoichiometries.
“the subunit composition presumably controls the affinity for nicotine, the extent of interaction with the ERAD machinery, the extent to which desensitization makes many additional states available, and the extent and stability of additional stoichiometries”
The paper relies on this without support.
2-[F18]fluoro-A-85380 binds well to α4β2* and α6* nAChRs.
“The positron emission tomography (PET) ligand, 2-[F18]fluoro-A-85380, binds well to α4β2* and to α6* nAChRs.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The cited source says what the claim attributes to it.
In the citing paper
“Nicotine appears to act intracellularly as a selective pharmacological chaperone of acetylcholine receptor (Lester et al. 2009).”
From Short- and Long-Term Consequences of Nicotine Exposure during Adolescence for Prefrontal Cortex Neuronal Network Function (2012) · cites this paper as Lester et al. 2009
The cited source says what the claim attributes to it.
In the citing paper
“The up-regulation of a4b2 nAChRs by chronic nicotine treatment has been replicated many times in numerous systems—transfected cell lines, neurons in culture, brain slices, and smokers’ brains (Wonnacott 1990; Fu et al. 2009; Lester et al. 2009; Marks et al. 2011; Miwa et al. 2011).”
From Short- and Long-Term Consequences of Nicotine Exposure during Adolescence for Prefrontal Cortex Neuronal Network Function (2012) · cites this paper as Lester et al. 2009
The cited source says what the claim attributes to it.
In the citing paper
“It stabilizes nAChRs during assembly and maturation and this stabilization is most pronounced for the highest-affinity nAChR containing α4β2 subunits.”
From Short- and Long-Term Consequences of Nicotine Exposure during Adolescence for Prefrontal Cortex Neuronal Network Function (2012) · cites this paper as Lester et al. 2009
In the citing paper
“Relevant to the understanding of the neuroadaptations produced by nicotine is the fact that nAChR upregulation differs among receptor subtypes, varies among brain regions for the same subtype, and even depends on the contingency of nicotine administration [9, 90, 93].”
From Mechanistic insights into nicotine withdrawal (2011) · cites this paper as [90]
In the citing paper
“Nicotine concentrations are elevated within ERGIC, TG/TGN, and secretory vesicles via acid trapping (Lester et al., 2009).”
From Nicotine up-regulates α4β2 nicotinic receptors and ER exit sites via stoichiometry-dependent chaperoning (2011) · cites this paper as Lester et al., 2009
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Abstract
“Even the lowest log P value, −0.4 for the competitive antagonist DHβE (Table 1), would allow it to penetrate eventually.”
§ Abstract
“X log P Dihydro-β˜-erythroidine −0.5 Cytisine −0.3”
Citations
Cites
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Balch, W. E., Morimoto, R. I., Dillin, A., & Kelly, J. W. (2008) · Science · doi:10.1126/science.1141448 · Cited by 2,495
A variant associated with nicotine dependence, lung cancer and peripheral arterial disease
Thorgeirsson, T. E., Geller, F., Sulem, P., Rafnar, T., Wiste, A., Magnusson, K. P., Manolescu, A., Thorleifsson, G., Stefansson, H., Ingason, A., et al. (2008) · Nature · doi:10.1038/nature06846 · Cited by 1,523
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Hung, R. J., McKay, J. D., Gaborieau, V., Boffetta, P., Hashibe, M., Zaridze, D., Mukeria, A., Szeszenia-Dabrowska, N., Lissowska, J., Rudnai, P., et al. (2008) · Nature · doi:10.1038/nature06885 · Cited by 1,275
Steinlein, O. K., Mulley, J. C., Propping, P., Wallace, R. H., Phillips, H. A., Sutherland, G. R., Scheffer, I. E., & Berkovic, S. F. (1995) · Nature Genetics · doi:10.1038/ng1095-201 · Cited by 1,134
Interaction of Tetraethylammonium Ion Derivatives with the Potassium Channels of Giant Axons
Armstrong, C. M. (1971) · The Journal of General Physiology · doi:10.1085/jgp.58.4.413 · Cited by 929
Brain nicotinic acetylcholine receptors: native subtypes and their relevance
Gotti, C., Zoli, M., & Clementi, F. (2006) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2006.07.004 · Cited by 882
Saccone, S. F., Hinrichs, A. L., Saccone, N. L., Chase, G. A., Konvicka, K., Madden, P. A. F., Breslau, N., Johnson, E. O., Hatsukami, D., Pomerleau, O., et al. (2007) · Human Molecular Genetics · doi:10.1093/hmg/ddl438 · Cited by 850 · cited 10×
“A second signal in the CHRNA5/A3/B4 cluster is tagged by SNP rs578776; it is strongly associated with nicotine dependence and has a low correlation with rs16969968 (r2= 0.18), indicating that it represents a statistically independent signal (90,91).”
BackgroundInfluentialSelf-citationGuidelines on nicotine dose selection for in vivo research
Matta, S. G., Balfour, D. J., Benowitz, N. L., Boyd, R. T., Buccafusco, J. J., Caggiula, A. R., Craig, C. R., Collins, A. C., Damaj, M. I., Donny, E. C., et al. (2007) · Psychopharmacology · doi:10.1007/s00213-006-0441-0 · Cited by 824
Research works printed but not linked: 2
- P. Liu, H. G. Vikis, D. Wang, Y. Lu, Y. Wang, A. G. Schwartz, S. M. Pinney, P. Yang, M. De Andrade, G. M. Petersen, J. S. Wiest, P. R. Fain, A. Gazdar, C. Gaba, H. Rothschild, D. Mandal, T. Coons, J. Lee, E. Kupert, D. Seminara, J. Minna, J. E. Bailey-Wilson, X. Wu, M. R. Spitz, T. Eisen, R. S. Houlston, C. I. Amos, M. W. Anderson, and M. You. Familial aggregation of common sequence variants on 15q24–25.1 in lung cancer. J Natl Cancer Inst. 100:1326–1330 (2008). · DOI · Paper page
- C. I. Amos, X. Wu, P. Broderick, I. P. Gorlov, J. Gu, T. Eisen, Q. Dong, Q. Zhang, X. Gu, J. Vijayakrishnan, K. Sullivan, A. Matakidou, Y. Wang, G. Mills, K. Doheny, Y. Y. Tsai, W. V. Chen, S. Shete, M. R. Spitz, and R. S. Houlston. Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1. Nat Genet. 40:616–622 (2008). · DOI · Paper page
Cited by
Sorted by citations
Nicotinic receptors: allosteric transitions and therapeutic targets in the nervous system
Taly, A., Corringer, P., Guédin, D., Lestage, P. J., & Changeux, J. (2009) · Nature Reviews Drug Discovery · doi:10.1038/nrd2927 · Cited by 743
“In this respect, it should be noted that nicotine and smoking-cessation drugs are usually tested under short-term conditions, while it is becoming clear that long-term chronic exposure to nicotine (and possibly to nicotinic drugs in general) could modify the levels of α4β2 versus α7 nAChR”
BackgroundX-ray structure of the human α4β2 nicotinic receptor
Morales-Pérez, C. L., Noviello, C., & Hibbs, R. E. (2016) · Nature · doi:10.1038/nature19785 · Cited by 413
Reward, addiction, withdrawal to nicotine
De Biasi, M., & Dani, J. A. (2011) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-061010-113734 · Cited by 366
“Therefore, nicotine can influence intracellular processes indirectly via nAChRs and directly by entering the cytoplasm (Lester et al. 2009, Rezvani et al. 2007).”
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“Nicotine appears to act intracellularly as a selective pharmacological chaperone of acetylcholine receptor (Lester et al. 2009).”
BackgroundStructural principles of distinct assemblies of the human α4β2 nicotinic receptor
Walsh, R. M., Roh, S., Gharpure, A., Morales-Pérez, C. L., Teng, J., & Hibbs, R. E. (2018) · Nature · doi:10.1038/s41586-018-0081-7 · Cited by 232
“The ratio of the two observed assemblies of the α 4 β 2 receptor in vivo is tunable and context-specific and is linked to genetic disorders and addiction 2–5 .”
Metadata
- Authors
- Lester, H. A., Xiao, C., Srinivasan, R., Son, C. D., Miwa, J., Pantoja, R., Banghart, M. R., Dougherty, D. A., Goate, A. M., & Wang, J. C.
- Affiliations
- California Institute of Technology (US)
- Harvard University (US)
- Washington University in St. Louis (US)
- Corresponding author
- Lester, Henry A.
- ORCID
- Venue
- The AAPS Journal
- Published
- 2009-03
- Volume
- 11
- Issue
- 1
- Pages
- 167-177
- ISSN
- 1550-7416 (ISSN-L)
- PMC
- PMC2664890
- OpenAlex
- W2083434249
- Semantic Scholar
- b9391525fc3ca03a6742aa0d414f0c2f757d6b9e
- Cited by
- 163
- References
- 131
- Citations by year
- 2025: 6 · 2024: 3 · 2023: 5 · 2022: 1 · 2021: 6 · 2020: 13 · 2019: 10 · 2018: 10 · 2017: 10 · 2016: 12 · 2015: 11 · 2014: 16 · 2013: 16 · 2012: 13
- FWCI
- 1.12
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- The AAPS Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion)
- OpenMETU (Middle East Technical University) (submittedVersion, cc-by-nc-nd)
- Funders
- National Institute on Alcohol Abuse and Alcoholism (AA08401, U10AA008401)
- National Institute on Aging (R01AG033954, AG033954)
- National Institute on Drug Abuse (DA-19375, U19DA019375, DA17279, R01DA017279)
- National Cancer Institute (CA089392, P01CA089392)
- National Institute of Neurological Disorders and Stroke (NS34407, NS 11756, R01NS034407, R01NS011756, R37NS034407)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- nicotine, pharmacological chaperones, nicotinic acetylcholine receptors, receptor stoichiometry, receptor density, receptor up-regulation, chronic nicotine exposure, nicotine dependence, neural adaptation, Parkinson's disease, nocturnal frontal lobe epilepsy, receptor desensitization, receptor maturation, subunit interface, proteostasis, lynx, drug discovery
- MeSH terms
- Acetylcholine, Animals, Endoplasmic Reticulum, Hippocampus, Models, Biological, Muscle Proteins, Nerve Tissue Proteins, Nicotine, Parkinson Disease, Receptors, Nicotinic, Smoking, Tobacco Use Disorder, Up-Regulation, Epilepsy, Frontal Lobe, Ventral Tegmental Area, Neurotransmitter Agents, Mutation, Missense, Mice, Drug Discovery
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-08, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-08 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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