The α4β2α5 nicotinic cholinergic receptor in rat brain is resistant to up‐regulation by nicotine in vivo

Mao, Danyan; Perry, David C.; Yasuda, Robert P.; Wolfe, Barry B.; Kellar, Kenneth J.

doi:10.1111/j.1471-4159.2007.05011.x

Cited by 133Nicotinic Acetylcholine Receptors StudySmoking Behavior and CessationNeuroscience and Neuropharmacology Research

The α4β2α5 nicotinic cholinergic receptor in rat brain is resistant to up‐regulation by nicotine in vivo

Mao, Danyan, Perry, David C., Yasuda, Robert P., Wolfe, Barry B., Kellar, Kenneth J.·2008·Journal of Neurochemistry

DOI 10.1111/j.1471-4159.2007.05011.x

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Abstract

We used immunoprecipitation with subunit-specific antibodies to examine the distribution of heteromeric neuronal nicotinic acetylcholine receptors (nAChRs) that contain the alpha5 subunit in the adult rat brain. Among the regions of brain we surveyed, the alpha5 subunit is associated in approximately 37% of the nAChRs in the hippocampus, approximately 24% of the nAChRs in striatum, and 11-16% of the receptors in the cerebral cortex, thalamus, and superior colliculus. Sequential immunoprecipitation assays demonstrate that the alpha5 subunit is associated with alpha4beta2* nAChRs exclusively. Importantly, in contrast to alpha4beta2 nAChRs, which are increased by 37-85% after chronic administration of nicotine, the alpha4beta2alpha5 receptors are not increased by nicotine treatment. These data thus indicate that the alpha4beta2alpha5 nAChRs in rat brain are resistant to up-regulation by nicotine in vivo, which suggests an important regulatory role for the alpha5 subunit. To the extent that nicotine-induced up-regulation of alpha4beta2 nAChRs is involved in nicotine addiction, the resistance of the alpha4beta2alpha5 subtype to up-regulation may have important implications for nicotine addiction.

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Different β2*-subunit combinations appear to be differentially regulated by nicotine, with α3/α6 and α6α4β2* and α5α4β2* not upregulating or decreasing in response to nicotine while α6β2 (nonα4) nAChR increase in response to nicotine.
“Importantly, different β2*-subunit combinations appear to be differentially regulated by nicotine, with α3/α6 and α6α4β2* and α5α4β2* not upregulating or decreasing in response to nicotine38, 85-88 while α6β2 (nonα4) nAChR increase in response to nicotine88.”
From β2-Nicotinic Acetylcholine Receptor Availability During Acute and Prolonged Abstinence From Tobacco Smoking (2009) · cites this paper as [38]
α5 makes α4β2* nAChRs insensitive to nicotine-induced upregulation.
“For example, the presence of α5 renders α4β2* nAChRs insensitive to nicotine-induced upregulation (Mao et al. 2008).”
From Nicotine Withdrawal (2015) · cites this paper as Mao et al. 2008
Chronic nicotine administration increases predominantly the α4β2 subtype of nAChRs in rodent brain.
“Immunoprecipitation with subunit-selective antibodies and studies in genetic knockout models demonstrate that chronic administration of nicotine increases predominantly the ␣4␤2 subtype of nAChRs in rodent brain (Flores et al., 1992;Mao et al., 2008;Moretti et al., 2010;Marks et al., 2011)”
From Chronic Sazetidine-A at Behaviorally Active Doses Does Not Increase Nicotinic Cholinergic Receptors in Rodent Brain (2012) · cites this paper as Mao et al., 2008
Different brain regions and nAChR subtypes have different upregulation parameters.
“While this prediction is straightforward, testing it has been confounded by the observation that different brain regions and nAChR subtypes have different upregulation parameters (Collins et al., 1989; Mao et al., 2008; Perry et al., 2007) and a lack of understanding of which brain regions are critically involved in specific withdrawal symptoms.”
From The duration of nicotine withdrawal-associated deficits in contextual fear conditioning parallels changes in hippocampal high affinity nicotinic acetylcholine receptor upregulation (2012) · cites this paper as Mao et al., 2008
The α5 subunit modifies upregulation of α4β2* receptors.
“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).”
From Nicotine is a selective pharmacological chaperone of acetylcholine receptor number and stoichiometry. Implications for drug discovery (2009) · cites this paper as [112]

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Brain Region Specific Single-Molecule Fluorescence Imaging
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Endogenously Expressed Muscarinic Receptors in HEK293 Cells Augment Up-regulation of Stably Expressed α4β2 Nicotinic Receptors
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3,4-Methylenedioxy-methamphetamine induces in vivo regional up-regulation of central nicotinic receptors in rats and potentiates the regulatory effects of nicotine on these receptors
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Choline Promotes Nicotinic Receptor α4 + β2 Up-regulation
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Nicotinic Receptor Subunit α5 Modifies Assembly, Up-regulation, and Response to Pro-inflammatory Cytokines
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Role of α5-containing nicotinic receptors in neuropathic pain and response to nicotine
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More than Smoke and Patches: The Quest for Pharmacotherapies to Treat Tobacco Use Disorder
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Synapse- and subtype-specific modulation of synaptic transmission by nicotinic acetylcholine receptors in the ventrobasal thalamus
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AT-1001 Is a Partial Agonist with High Affinity and Selectivity at Human and Rat α3β4 Nicotinic Cholinergic Receptors
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Blockade of nicotinic acetylcholine receptor enhances the responsiveness to bupropion in the mouse forced swim test
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A subtype of nicotinic cholinergic receptor in rat brain is composed of alpha 4 and beta 2 subunits and is up-regulated by chronic nicotine treatment.
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Authors: Mao, D., Perry, D. C., Yasuda, R. P., Wolfe, B. B., & Kellar, K. J.
Affiliations: Georgetown University (US)
George Washington University (US)
Corresponding author: Kellar, Kenneth J.
ORCID: Perry, David C.
Kellar, Kenneth J.
Venue: Journal of Neurochemistry
Publisher: Wiley
Published: 2007-09-26
Volume: 104
Issue: 2
Pages: 446-456
ISSN: 0022-3042 (ISSN-L)
1471-4159
DOI: 10.1111/j.1471-4159.2007.05011.x
OpenAlex: W1976309270
Cited by: 133
References: 57
Citations by year: 2026: 3 · 2024: 2 · 2023: 2 · 2022: 2 · 2021: 4 · 2020: 4 · 2019: 4 · 2018: 7 · 2017: 4 · 2016: 11 · 2015: 11 · 2014: 11 · 2013: 12 · 2012: 14
FWCI: 4.33
Type: journal article
Language: en
Open access: closed
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations: Journal of Neurochemistry (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health
National Institute on Drug Abuse (R01DA015767, DA015767, DA 12976)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
Health Sciences › Medicine › Physiology › Smoking Behavior and Cessation
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords: nicotinic acetylcholine receptors, alpha5 subunit, receptor up-regulation, nicotine, receptor subunit composition, hippocampus, striatum, cerebral cortex, thalamus, superior colliculus, nicotine dependence, rat brain
MeSH terms: Animals, Binding Sites, Brain, Nicotine, Pyridines, Receptors, Nicotinic, Up-Regulation, Rats, Sprague-Dawley, Nicotinic Agonists, Bridged Bicyclo Compounds, Heterocyclic, Protein Subunits, Immunoprecipitation, Rats

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The α4β2α5 nicotinic cholinergic receptor in rat brain is resistant to up‐regulation by nicotine in vivo

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