Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
J Pharmacol Exp Ther
2014 Mar 01;3483:410-20. doi: 10.1124/jpet.113.209767.
Show Gene links
Show Anatomy links
Rare human nicotinic acetylcholine receptor α4 subunit (CHRNA4) variants affect expression and function of high-affinity nicotinic acetylcholine receptors.
McClure-Begley TD
,
Papke RL
,
Stone KL
,
Stokes C
,
Levy AD
,
Gelernter J
,
Xie P
,
Lindstrom J
,
Picciotto MR
.
???displayArticle.abstract???
Nicotine, the primary psychoactive component in tobacco smoke, produces its behavioral effects through interactions with neuronal nicotinic acetylcholine receptors (nAChRs). α4β2 nAChRs are the most abundant in mammalian brain, and converging evidence shows that this subtype mediates the rewarding and reinforcing effects of nicotine. A number of rare variants in the CHRNA4 gene that encode the α4 nAChR subunit have been identified in human subjects and appear to be underrepresented in a cohort of smokers. We compared three of these variants (α4R336C, α4P451L, and α4R487Q) to the common variant to determine their effects on α4β2 nAChR pharmacology. We examined [(3)H]epibatidine binding, interacting proteins, and phosphorylation of the α4 nAChR subunit with liquid chromatography and tandem mass spectrometry (LC-MS/MS) in HEK 293 cells and voltage-clamp electrophysiology in Xenopus laevis oocytes. We observed significant effects of the α4 variants on nAChR expression, subcellular distribution, and sensitivity to nicotine-induced receptor upregulation. Proteomic analysis of immunopurified α4β2 nAChRs incorporating the rare variants identified considerable differences in the intracellular interactomes due to these single amino acid substitutions. Electrophysiological characterization in X. laevis oocytes revealed alterations in the functional parameters of activation by nAChR agonists conferred by these α4 rare variants, as well as shifts in receptor function after incubation with nicotine. Taken together, these experiments suggest that genetic variation at CHRNA4 alters the assembly and expression of human α4β2 nAChRs, resulting in receptors that are more sensitive to nicotine exposure than those assembled with the common α4 variant. The changes in nAChR pharmacology could contribute to differences in responses to smoked nicotine in individuals harboring these rare variants.
Benowitz,
Pharmacology of nicotine: addiction and therapeutics.
1996, Pubmed
Benowitz,
Pharmacology of nicotine: addiction and therapeutics.
1996,
Pubmed
Bierut,
Variants in nicotinic receptors and risk for nicotine dependence.
2008,
Pubmed
Gotti,
Partial deletion of the nicotinic cholinergic receptor alpha 4 or beta 2 subunit genes changes the acetylcholine sensitivity of receptor-mediated 86Rb+ efflux in cortex and thalamus and alters relative expression of alpha 4 and beta 2 subunits.
2008,
Pubmed
Han,
Association of CHRNA4 polymorphisms with smoking behavior in two populations.
2011,
Pubmed
Han,
Meta-analysis of 15 genome-wide linkage scans of smoking behavior.
2010,
Pubmed
Harkness,
Changes in conformation and subcellular distribution of alpha4beta2 nicotinic acetylcholine receptors revealed by chronic nicotine treatment and expression of subunit chimeras.
2002,
Pubmed
Hu,
Epidemiology and correlates of daily smoking and nicotine dependence among young adults in the United States.
2006,
Pubmed
Jeanclos,
The chaperone protein 14-3-3eta interacts with the nicotinic acetylcholine receptor alpha 4 subunit. Evidence for a dynamic role in subunit stabilization.
2001,
Pubmed
,
Xenbase
Jia,
Nicotine trapping causes the persistent desensitization of alpha4beta2 nicotinic receptors expressed in oocytes.
2003,
Pubmed
,
Xenbase
Kamens,
Nominal association with CHRNA4 variants and nicotine dependence.
2013,
Pubmed
Kracun,
Influence of the M3-M4 intracellular domain upon nicotinic acetylcholine receptor assembly, targeting and function.
2008,
Pubmed
Kukhtina,
Intracellular domain of nicotinic acetylcholine receptor: the importance of being unfolded.
2006,
Pubmed
Kuo,
Roles for nicotinic acetylcholine receptor subunit large cytoplasmic loop sequences in receptor expression and function.
2005,
Pubmed
Kuryatov,
Nicotine acts as a pharmacological chaperone to up-regulate human alpha4beta2 acetylcholine receptors.
2005,
Pubmed
Kuryatov,
Acetylcholine receptor (AChR) α5 subunit variant associated with risk for nicotine dependence and lung cancer reduces (α4β2)₂α5 AChR function.
2011,
Pubmed
,
Xenbase
Lester,
Nicotine is a selective pharmacological chaperone of acetylcholine receptor number and stoichiometry. Implications for drug discovery.
2009,
Pubmed
Lukas,
International Union of Pharmacology. XX. Current status of the nomenclature for nicotinic acetylcholine receptors and their subunits.
1999,
Pubmed
Marks,
86Rb+ efflux mediated by alpha4beta2*-nicotinic acetylcholine receptors with high and low-sensitivity to stimulation by acetylcholine display similar agonist-induced desensitization.
2010,
Pubmed
Marks,
Two pharmacologically distinct components of nicotinic receptor-mediated rubidium efflux in mouse brain require the beta2 subunit.
1999,
Pubmed
Marks,
Gene targeting demonstrates that alpha4 nicotinic acetylcholine receptor subunits contribute to expression of diverse [3H]epibatidine binding sites and components of biphasic 86Rb+ efflux with high and low sensitivity to stimulation by acetylcholine.
2007,
Pubmed
McGranahan,
α4β2 nicotinic acetylcholine receptors on dopaminergic neurons mediate nicotine reward and anxiety relief.
2011,
Pubmed
Millar,
Diversity of vertebrate nicotinic acetylcholine receptors.
2009,
Pubmed
Moroni,
Stoichiometry and pharmacology of two human alpha4beta2 nicotinic receptor types.
2006,
Pubmed
,
Xenbase
Nelson,
Alternate stoichiometries of alpha4beta2 nicotinic acetylcholine receptors.
2003,
Pubmed
,
Xenbase
Nishimura,
A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis.
2004,
Pubmed
Pacheco,
Phosphorylation of the alpha4 subunit of human alpha4beta2 nicotinic receptors: role of cAMP-dependent protein kinase (PKA) and protein kinase C (PKC).
2003,
Pubmed
Papke,
Single-channel currents of rat neuronal nicotinic acetylcholine receptors expressed in Xenopus oocytes.
1989,
Pubmed
,
Xenbase
Picciotto,
Acetylcholine receptors containing the beta2 subunit are involved in the reinforcing properties of nicotine.
1998,
Pubmed
Picciotto,
Abnormal avoidance learning in mice lacking functional high-affinity nicotine receptor in the brain.
1995,
Pubmed
Pollock,
Cyclic AMP-dependent protein kinase (PKA) phosphorylates Ser362 and 467 and protein kinase C phosphorylates Ser550 within the M3/M4 cytoplasmic domain of human nicotinic receptor alpha4 subunits.
2007,
Pubmed
Pollock,
Cyclic AMP-dependent protein kinase A and protein kinase C phosphorylate alpha4beta2 nicotinic receptor subunits at distinct stages of receptor formation and maturation.
2009,
Pubmed
Pomerleau,
Development and validation of a self-rating scale for positive- and negative-reinforcement smoking: The Michigan Nicotine Reinforcement Questionnaire.
2003,
Pubmed
Richards,
Trafficking of alpha4* nicotinic receptors revealed by superecliptic phluorin: effects of a beta4 amyotrophic lateral sclerosis-associated mutation and chronic exposure to nicotine.
2011,
Pubmed
Sabatelli,
Replication of association of CHRNA4 rare variants with sporadic amyotrophic lateral sclerosis: the Italian multicentre study.
2012,
Pubmed
Sabatelli,
Rare missense variants of neuronal nicotinic acetylcholine receptor altering receptor function are associated with sporadic amyotrophic lateral sclerosis.
2009,
Pubmed
Saha,
Investigating diproline segments in proteins: occurrences, conformation and classification.
2012,
Pubmed
Srinivasan,
Nicotine up-regulates alpha4beta2 nicotinic receptors and ER exit sites via stoichiometry-dependent chaperoning.
2011,
Pubmed
Staley,
Human tobacco smokers in early abstinence have higher levels of beta2* nicotinic acetylcholine receptors than nonsmokers.
2006,
Pubmed
Stitzel,
Potential role of the alpha4 and alpha6 nicotinic receptor subunits in regulating nicotine-induced seizures.
2000,
Pubmed
Stitzel,
Long sleep and short sleep mice differ in nicotine-stimulated 86Rb+ efflux and alpha4 nicotinic receptor subunit cDNA sequence.
2001,
Pubmed
Tapper,
Nicotine activation of alpha4* receptors: sufficient for reward, tolerance, and sensitization.
2004,
Pubmed
Tapper,
Nicotine responses in hypersensitive and knockout alpha 4 mice account for tolerance to both hypothermia and locomotor suppression in wild-type mice.
2007,
Pubmed
Tsetlin,
Assembly of nicotinic and other Cys-loop receptors.
2011,
Pubmed
Wecker,
Cyclic AMP-dependent protein kinase (PKA) and protein kinase C phosphorylate sites in the amino acid sequence corresponding to the M3/M4 cytoplasmic domain of alpha4 neuronal nicotinic receptor subunits.
2001,
Pubmed
,
Xenbase
Whiting,
Characterization of bovine and human neuronal nicotinic acetylcholine receptors using monoclonal antibodies.
1988,
Pubmed
Wilking,
Chrna4 A529 knock-in mice exhibit altered nicotine sensitivity.
2010,
Pubmed
Williams,
The effective opening of nicotinic acetylcholine receptors with single agonist binding sites.
2011,
Pubmed
,
Xenbase
Xie,
Rare nonsynonymous variants in alpha-4 nicotinic acetylcholine receptor gene protect against nicotine dependence.
2011,
Pubmed
Zhou,
Human alpha4beta2 acetylcholine receptors formed from linked subunits.
2003,
Pubmed
,
Xenbase
Zwart,
Four pharmacologically distinct subtypes of alpha4beta2 nicotinic acetylcholine receptor expressed in Xenopus laevis oocytes.
1998,
Pubmed
,
Xenbase
