The nicotinic acetylcholine receptor CHRNA5/A3/B4 gene cluster: Dual role in nicotine addiction and lung cancer

Abstract

More than 1 billion people around the world smoke, with 10 million cigarettes sold every minute. Cigarettes contain thousands of harmful chemicals including the psychoactive compound, nicotine. Nicotine addiction is initiated by the binding of nicotine to nicotinic acetylcholine receptors, ligand-gated cation channels activated by the endogenous neurotransmitter, acetylcholine. These receptors serve as prototypes for all ligand-gated ion channels and have been extensively studied in an attempt to elucidate their role in nicotine addiction. Many of these studies have focused on heteromeric nicotinic acetylcholine receptors containing α4 and β2 subunits and homomeric nicotinic acetylcholine receptors containing the α7 subunit, two of the most abundant subtypes expressed in the brain. Recently however, a series of linkage analyses, candidate-gene analyses and genome-wide association studies have brought attention to three other members of the nicotinic acetylcholine receptor family: the α5, α3 and β4 subunits. The genes encoding these subunits lie in a genomic cluster that contains variants associated with increased risk for several diseases including nicotine dependence and lung cancer. The underlying mechanisms for these associations have not yet been elucidated but decades of research on the nicotinic receptor gene family as well as emerging data provide insight on how these receptors may function in pathological states. Here, we review this body of work, focusing on the clustered nicotinic acetylcholine receptor genes and evaluating their role in nicotine addiction and lung cancer.

Alanine Scan of α-Conotoxin RegIIA Reveals a Selective α3β4 Nicotinic Acetylcholine Receptor Antagonist

“…It also identifies key residues such as Asn 9 , Asn 11 , and Asn 12 involved in toxin-receptor interaction. This information will be valuable in the design and development of potent, ␣3␤4-selective drugs to treat lung cancer and nicotine addiction.…”

“…8). Two studies identified tobacco-specific nitrosamines as potent nAChR agonists and inhibitors of cancer cell apoptosis (9). In addition, genome-wide studies identified associations between lung cancer and several single nucleotide polymorphisms within the gene cluster encoding the ␣3, ␣5, and ␤4 nAChR subunits (10).…”

Patterns of Nicotinic Receptor Antagonism: Nicotine Discrimination Studies

“…Drug discrimination assays have been used in attempts to isolate the receptor that is most relevant to nicotine's interoceptive effects, and several lines of evidence indicate that these are also mediated through the ␣4␤2 subtype of the nAChR (for review, see Smith and Stolerman, 2009). Nevertheless, genetic studies in particular have implicated other nicotinic receptor subtypes, such as the ␣3, ␣5, ␣6, and ␤4 subunits, in the abuse liability of nicotine (Improgo et al, 2010;Sherva et al, 2010;Russo et al, 2011).…”

Response to Transdermal Selegiline Smoking Cessation Therapy and Markers in the 15q24 Chromosomal Region

“…CHRNB4 contains a 3′ enhancer element involved in this combined regulation. 47,48 The rs3813567 major T allele was reported to be associated with risk for smoking, 49 but those results were not based on a selegiline clinical trial. Our results indicate that during selegiline treatment it was the C minor allele that was over-represented among those not abstinent.…”