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Cited by 164Nicotinic Acetylcholine Receptors StudyReceptor Mechanisms and SignalingNeuroscience and Neuropharmacology Research

Nicotine is a selective pharmacological chaperone of acetylcholine receptor number and stoichiometry. Implications for drug discovery

Open access
Lester, Henry A., Xiao, Cheng, Srinivasan, Rahul, Son, Cagdas D., Miwa, Julie, Pantoja, Rigo, Banghart, Matthew R., Dougherty, Dennis A. +2 more·2009·The AAPS Journal
DOI 10.1208/s12248-009-9090-7PMC PMC2664890
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Abstract

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.

AI snapshot

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.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1208/s12248-009-9090-7

Cites

131 of 131 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 172 cited sources checked · 0 supported · 0 flagged

  • Findingcitation
    § Abstract

    Chronic exposure to nicotine increases α4* receptors on glutamatergic axons of the medial perforant path.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • Findingcitation
    § Abstract

    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.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • Findingcitation
    § Abstract

    This upregulation produces higher GABAergic SNr neuron firing rate, even in the absence of nicotine.

    “This upregulation produces higher GABAergic SNr neuron firing rate, even in the absence of nicotine (5).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • Findingcitation
    § Abstract

    Increased nAChR sensitivity after chronic nicotine is found both in the somata and in the synaptic terminals of mouse SNr GABAergic neurons.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites C. Xiao and H. Lester, unpublished

      Not checked in the free run.

  • Findingcitation
    § Abstract

    Five ADNFLE receptors have an additional common abnormality: the intracellular pool of mutant receptors is shifted toward the (α4)3(β2)2 stoichiometry.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites C. Son, F. Moss, B. N. Cohen, H. A. Lester, submitted

      Not checked in the free run.

  • May combine two claims. 41
  • Classified as probably not a substantial claim. 27

  • May combine two claims.

    Findingcitation
    § Abstract

    Chronic nicotine increases both the baseline firing rate and the excitatory effect of nicotine in GABAergic VTA neurons, while decreasing baseline firing rate and attenuating the excitatory effect of nicotine in dopaminergic VTA neurons.

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • May combine two claims.

    Findingcitation
    § Abstract

    Chronic nicotine exposure cell-selectively upregulates receptor numbers in GABAergic neurons of the ventral tegmental area (VTA), but not in the somata of dopaminergic neurons.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • May combine two claims.

    Findingcitation
    § Abstract

    The augmentation of long-term potentiation by acute nicotine during tetanus in the medial perforant path is absent when chronic nicotine exposure is omitted, when acute exposure during the tetanus is omitted, or both.

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • May combine two claims.

    Findingreasoning
    § Abstract

    SNc DA neurons from chronic nicotine-treated mice have a lower baseline firing rate and a lower incidence of burst firing.

    “In consequence, SNc DA neurons from chronic nicotine-treated mice have a lower baseline firing rate and a lower incidence of burst firing.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • May combine two claims.

    Findingcitation
    § Abstract

    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).

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • May combine two claims.

    Findingcitation
    § Abstract

    Experiments with cultures from α4-hypersensitive mice show that upregulation occurs at chronic nicotine concentrations that activate only α4* receptors, in homotypic GABAergic cultures lacking their typical presynaptic partners, and when tested with ACh concentrations that activate only the α4* receptors.

    “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).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [48] R. Nashmi, and H. Lester. Cell autonomy, receptor autonomy, and thermodynamics in nicotine receptor up-regulation. Biochem Pharmacol. 74:1145–1154 (2007). source

      Not checked in the free run.

    • cites [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

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationcitation
    § Abstract

    Increases in inhibition could provide an explanation for tolerance to the chronic effects of nicotine.

    “and that increases in inhibition could provide an explanation for tolerance to the chronic effects of nicotine (5).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • May combine two claims.

    Premisecitation
    § Abstract

    α4β2* nAChRs are selectively upregulated by chronic nicotine, but other nAChR subtypes are also upregulated.

    “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);”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Abstract

    Nicotine makes neither the cation-π nor the hydrogen-bond interaction with the muscle receptor.

    “Nicotine makes neither interaction with the muscle receptor (45,46).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning
    § Abstract

    Nicotine can enter the endoplasmic reticulum and other organelles.

    “This implies that nicotine can also enter the endoplasmic reticulum and other organelles.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning
    § Abstract

    If ACh survived for several hours near neurons, it too would produce SePhaChARNS.

    “If ACh survived for several hours near neurons (which is not the case), it too would produce SePhaChARNS.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data
    § Abstract

    The in vitro effect of nicotine on ADNFLE receptor stoichiometry brings partial rationalization to its in vivo effect and suggests new clues about the pathophysiology.

    “However, the in vitro effect of nicotine brings partial rationalization to its in vivo effect and suggests new clues about the pathophysiology.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites C. Son, F. Moss, B. N. Cohen, H. A. Lester, submitted

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Abstract

    Quaternary amines with substantial hydrophobic substituents display detectable membrane permeability.

    “Quaternary amines with substantial hydrophobic substituents also display detectable membrane permeability; this is revealed in the literature on blockers of voltage-gated ion channels.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation
    § Abstract

    These effects on dopaminergic terminals extend and confirm other reports that chronic nicotine increases nicotine-induced dopamine release and upregulates receptors in striatum.

    “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).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

  • May combine two claims.

    Premisecitation
    § Abstract

    Nicotine is metabolized only by liver enzymes and disappears from blood with a half-life of ~120 min.

    “Nicotine is metabolized only by liver enzymes and disappears from blood with a half-life of ~120 min (35).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Abstract

    The EC50 for nicotine at (α4)2(β2)3 neuronal receptors is ~1 μM; at (α1)2β1γδ muscle receptors, ~400 μM.

    “The EC50 for nicotine at (α4)2(β2)3 neuronal receptors is ~1 μM; at (α1)2β1γδ muscle receptors, ~ 400 μM.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisenone given
    § Abstract

    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.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning
    § Abstract

    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.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § Abstract

    Hexamethonium, mecamylamine, or decamethonium by themselves do not produce appreciable up-regulation.

    “Unsurprisingly, hexamethonium, mecamylamine, or decamethonium by themselves do not produce appreciable up-regulation (54,65).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given
    § Abstract

    An effective pharmacological chaperone for nAChRs must be present at concentrations greater than its equilibrium dissociation constant for the nAChR subtype (including the particular stoichiometry) that it will chaperone.

    “(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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § Abstract

    Neither hexamethonium nor chlorisondamine are foot-in-the-door blockers at high-sensitivity α4β2 receptors.

    “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;”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning
    § Abstract

    These differences show how nicotine can activate and upregulate (α4)2(β2)3 receptors but have minimal effect on muscle receptors.

    “These differences show how nicotine can activate and upregulate (α4)2(β2)3 receptors but have minimal effect on muscle receptors.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given
    § Abstract

    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.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning
    § Abstract

    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.

    “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.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given
    § Abstract

    An effective pharmacological chaperone for nAChRs should bind at one or more subunit interfaces in the pentameric complex, so that it can stabilize the assembled rather than unassembled receptor.

    “(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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § Abstract

    Several studies suggest that the high- and low-sensitivity forms of α4β2 receptors 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.

    “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).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationcitation
    § Abstract

    These observations agree well with the SePhaChARNS mechanism, which makes no explicit statements about agonists vs antagonists.

    “These observations agree well with the SePhaChARNS mechanism, which makes no explicit statements about agonists vs antagonists.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Abstract

    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.

    “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).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

  • May combine two claims.

    Premisecitation
    § Abstract

    Mecamylamine lacks foot-in-the-door properties at ganglionic nAChRs and has not been evaluated for such properties at α4β2 receptors.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Abstract

    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.

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [48] R. Nashmi, and H. Lester. Cell autonomy, receptor autonomy, and thermodynamics in nicotine receptor up-regulation. Biochem Pharmacol. 74:1145–1154 (2007). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationreasoning
    § Abstract

    An effective pharmacological chaperone for nAChRs must penetrate to the lumen of the endoplasmic reticulum.

    “Here are the requirements for an effective pharmacological chaperone for nAChRs. (1) The drug must penetrate to the lumen of the endoplasmic reticulum.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § Abstract

    Upregulation induced in animal models and transfected cells by chronic nicotine is certainly not transcriptional and is probably post-translational.

    “Upregulation induced in animal models and transfected cells by chronic nicotine is certainly not transcriptional and is probably post-translational (47).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § Abstract

    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.

    “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.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [78] A. Roos, and W. F. Boron. Intracellular pH. Physiol. Rev. 61:296–434 (1981). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Abstract

    Exocytosis is required for upregulation, presumably because exocytosis is downstream from SePhaChARNS.

    “Exocytosis is required for upregulation, presumably because exocytosis is downstream from SePhaChARNS (53).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning
    § Abstract

    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.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § Abstract

    Human α4 harboring a Ser247Phe mutation renders the channel nonfunctional in HEK tsA201 cells, yet chronic nicotine induces robust upregulation of the receptor in this clonal cell line.

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Abstract

    The most thoroughly investigated and replicated finding to date is the association with rs16969968 in CHRNA5.

    “The most thoroughly investigated and replicated finding to date is the association with rs16969968, in CHRNA5 (91).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning
    § Abstract

    If receptor assembly and function in the secretory pathway is approximately normal, then in the presence of smoked nicotine receptors are primarily in a desensitized state before they reach the cell surface.

    “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.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: The assembly and function of receptors within the secretory pathway is approximately normal.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Abstract

    Small-molecule proteostasis regulators stabilize the misfolding-prone ΔF508 mutant of the cystic fibrosis transmembrane conductance regulator.

    “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).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [83] Www.Clinicaltrials.Gov . [cited.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Abstract

    SNP rs578776 is strongly associated with nicotine dependence and has a low correlation with rs16969968 (r2 = 0.18), indicating that it represents a statistically independent signal.

    “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).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S1 (asserted).

    Premisecitation
    § Abstract

    Stabilization of high-affinity nicotinic receptors by chronic nicotine is a thermodynamic necessity.

    “Thus, in one view, stabilization of high-affinity nicotinic receptors by chronic nicotine is a thermodynamic necessity (48).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [48] R. Nashmi, and H. Lester. Cell autonomy, receptor autonomy, and thermodynamics in nicotine receptor up-regulation. Biochem Pharmacol. 74:1145–1154 (2007). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationnone given
    § Abstract

    SePhaChARNS does not explicitly include nicotine-evoked changes in endocytosis or exocytosis.

    “Second, SePhaChARNS does not explicitly include nicotine-evoked changes in endocytosis or exocytosis.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationreasoning
    § Abstract

    α4β2 receptors, in the absence of additional subunits, may be more amenable to SePhaChARNS than other subtypes.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning
    § Abstract

    Noncoding mutations such as rs578776 could affect the level of expression of the α5 protein, thereby affect the proportion of α4β2* receptors that are α4β2α5* receptors, and thus also affect chaperoning.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § Abstract

    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.

    “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).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Abstract

    Lynx1KO mice demonstrate cognitive enhancements and neurological changes.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Abstract

    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.

    “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).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § Abstract

    SLURP1 is expressed in the periphery, not in neurons, is not GPI anchored, but is secreted out of the cell.

    “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).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Abstract

    SLURP-1 is mutated in Mal de Meleda.

    “For example, SLURP-1 is mutated in Mal de Meleda (120).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Abstract

    In lung, lynx1 is co-expressed with nAChRs.

    “In lung, lynx1 is co-expressed with nAChRs (125).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationreasoning
    § Abstract

    A key lynx-nAChR interaction may occur during receptor biosynthesis and maturation, in addition to acute nicotine-receptor interactions at the surface membrane.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § Abstract

    Aging lynx1 KO mice undergo a striatal degeneration that 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.

    “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).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § Abstract

    Other reports indicate an increased risk of lung cancer even in nonsmokers, suggesting the possibility of a direct effect on lung cancer vulnerability.

    “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).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationreasoning
    § Abstract

    SePhaChARNS could be manipulated by drugs that modify protein chaperones.

    “It is also possible that SePhaChARNS could be manipulated by drugs that modify protein chaperones.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing).

    Premisecitation
    § Abstract

    Some reports indicate that the association with lung cancer could be explained through an indirect effect on risk for smoking.

    “some indicate that the association could be explained through an indirect effect on risk for smoking (96)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • May combine two claims.

    Premisecitation
    § Abstract

    Bronchial epithelium, squamous cell lung carcinoma, non-small-cell lung cancers, and BEP2D cells express α5 subunits.

    “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.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Abstract

    Other studies on α5 knockout mice show changes in both presynaptic and somatodendritic nAChR responses.

    “Other studies on α5 knockout mice show changes in both presynaptic and somatodendritic nAChR responses (111).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationreasoning
    § Abstract

    The rs16969968 coding-region mutation in the M3-M4 cytoplasmic loop could interact with ERAD machinery to alter chaperoning.

    “The rs16969968, coding-region mutation, in the M3–M4 cytoplasmic loop, could interact with ERAD machinery to alter chaperoning.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationcitation
    § Abstract

    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.

    “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).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning
    § Abstract

    One may best discover drugs that affect SePhaChARNS by studying events in the ER.

    “Thus, one may best discover drugs that affect SePhaChARNS by studying events in the ER.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § Abstract

    SLURPs enhance nicotine-stimulated proliferation of lymphocytes and keratinocytes as well as oral and lung cancer cell proliferation.

    “SLURPs enhance this process (123) as well as oral and lung cancer cell proliferation (124).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning
    § Abstract

    Lynx proteins oppose some of the effects of chronic nicotine exposure and have a desensitizing influence on nAChRs.

    “Furthermore, they suggest that lynx proteins oppose some of the effects of chronic nicotine exposure, and have a desensitizing influence on nAChRs.”
    Quote in the paperNot a substantial claim
62 of 62

  • 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.”
6 of 6

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?

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.

  • DHβE log P differs from Table I

    Minor

    The text gives DHβE a log P of −0.4, but Table I lists dihydro-β-erythroidine at −0.5.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 2

  1. 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
  2. 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

Related

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
Publisher
Springer Science and Business Media LLC
Published
2009-03
Volume
11
Issue
1
Pages
167-177
ISSN
1550-7416 (ISSN-L)
DOI
10.1208/s12248-009-9090-7
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
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.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-08.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-08.

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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