ArticleThe Journal of pharmacology and experimental therapeutics2014
Rare human nicotinic acetylcholine receptor α4 subunit (CHRNA4) variants affect expression and function of high-affinity nicotinic acetylcholine receptors.
Article in The Journal of pharmacology and experimental therapeutics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers, 2 of them syntheses that pooled it.
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Who cites it
13 citing papers in PubMed, 2 syntheses or guidelines pooled it, 35 citations in OpenAlex.
- Exome Chip Meta-analysis Fine Maps Causal Variants and Elucidates the Genetic Architecture of Rare Coding Variants in Smoking and Alcohol Use.Biological psychiatry · 2019Pooled it
- Genome-wide meta-analysis reveals common splice site acceptor variant in CHRNA4 associated with nicotine dependence.Translational psychiatry · 2015Pooled it
- Importance of Modulating Kynurenic Acid Metabolism-Approaches for the Treatment of Dementia.Biomolecules · 2025Review
- A potential cost of evolving epibatidine resistance in poison frogs.BMC biology · 2023Article
- Human Genetics of Addiction: New Insights and Future Directions.Current psychiatry reports · 2018Review
- Insights Into Nicotinic Receptor Signaling in Nicotine Addiction: Implications for Prevention and Treatment.Current neuropharmacology · 2018Review
- Evidence for Association Between Low Frequency Variants in CHRNA6/CHRNB3 and Antisocial Drug Dependence.Behavior genetics · 2016Article
- CHRNA4 and ANKK1 Polymorphisms Influence Smoking-Induced Nicotinic Acetylcholine Receptor Upregulation.Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco · 2016Article
- A rare missense mutation in CHRNA4 associates with smoking behavior and its consequences.Molecular psychiatry · 2016Article
- Nicotinic acetylcholine receptors: upregulation, age-related effects and associations with drug use.Genes, brain, and behavior · 2016Review
- Natural genetic variability of the neuronal nicotinic acetylcholine receptor subunit genes in mice: Consequences and confounds.Neuropharmacology · 2015Review
- Nicotinic receptor contributions to smoking: insights from human studies and animal models.Current addiction reports · 2015Article
- Functional characterization improves associations between rare non-synonymous variants in CHRNB4 and smoking behavior.PloS one · 2014Article
Corrections and comments
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Authors and funding
9 authors at 7 institutions in 1 country.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.