The CHRNA5/A3/B4 Gene Cluster Variability as an Important Determinant of Early Alcohol and Tobacco Initiation in Young Adults

Schlaepfer, Isabel R.; Hoft, Nicole R.; Collins, Allan C.; Corley, Robin P.; Hewitt, John K.; Hopfer, Christian J.; Lessem, Jeffrey M.; McQueen, Matthew B.; Rhee, Soo Hyun; Ehringer, Marissa A.

doi:10.1016/j.biopsych.2007.10.024

Cited by 175 publications

(190 citation statements)

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“…Additional research has demonstrated associations between the CHRNA5-CHRNA3-CHRNB4 gene cluster and smoking initiation (e.g. smoking at least once a month); 1 SNPs in CHRNA5 (rs514743), 1 SNP in CHRNB4 (rs1948), and an intergenic SNP located between CHRNA3 and CHRNB4 (rs8023462) were associated with an earlier age of smoking initiation and were replicated in an independent sample [150].…”

Section: The Chrnb3-chrna6 and Chrna5-chrna3-chrnb4 Gene Clustersmentioning

confidence: 88%

Genetic variability in nicotinic acetylcholine receptors and nicotine addiction: Converging evidence from human and animal research

Portugal

Gould

2008

Behavioural Brain Research

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Tobacco smoking is a leading preventable cause of death in the United States and produces a major health and economic burden. Although the majority of smokers want to quit, few are successful. These data highlight the need for additional research into the neurobiology of tobacco dependence. Addiction to nicotine, the main psychoactive component of tobacco, is influenced by multiple factors that include individual differences in genetic makeup. Twin studies have demonstrated that genetic factors can influence vulnerability to nicotine addiction, and subsequent research has identified genes that may alter sensitivity to nicotine. In humans, genome-wide and candidate gene association studies have demonstrated that genes encoding nicotinic acetylcholine receptor (nAChR) proteins are associated with multiple smoking phenotypes. Similarly, research in mice has provided evidence that naturally occurring variability in nAChR genes is associated with changes in nicotine sensitivity. Furthermore, the use of genetic knockout mice has allowed researchers to determine the nAChR genes that mediate the effects of nicotine, whereas research with knockin mice has demonstrated that changes to nAChR genes can dramatically alter nicotine sensitivity. This review will examine the genetic factors that alter susceptibility to nicotine addiction, with an emphasis on the genes that encode nAChR proteins.

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Section: The Chrnb3-chrna6 and Chrna5-chrna3-chrnb4 Gene Clustersmentioning

confidence: 88%

Genetic variability in nicotinic acetylcholine receptors and nicotine addiction: Converging evidence from human and animal research

Portugal

Gould

2008

Behavioural Brain Research

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“…12,81 Age of SI (and its influence on later life smoking behavior) is another phenotype that has been studied from the genetic perspective (Table 2). 82,83 Development of ND requires exposure to nicotine. Therefore, the most appropriate controls for studying factors that influence severity of ND in smokers are individuals who initiated smoking and had sufficient exposure to develop ND but did not.…”

Section: Genetics Of Nd-related Phenotypesmentioning

confidence: 99%

“…Comorbidity of nicotine and alcohol use is well documented but a common biological mechanism or genetic background has not been shown. 9,83 Association of the CHRNA5-CHRNA3-CHRNB4 locus with alcohol dependence (defined by DSM-IV) was shown for 16 polymorphisms (out of 42 genotyped) in two samples, spanning the CHRNA5-CHRNA3 region and including a SNP (rs588765) that affects mRNA levels. 94 These variants show low LD with most other ND associated SNPs reported earlier.…”

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confidence: 99%

Differential contribution of genetic variation in multiple brain nicotinic cholinergic receptors to nicotine dependence: recent progress and emerging open questions

Greenbaum¹,

Lerer²

2009

Mol Psychiatry

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Nicotine dependence (ND), a major public health challenge, is a complex, multifactorial behavior, in which both genetic and environmental factors have a role. Brain nicotinic acetylcholine receptor (nAChR)-encoding genes are among the most prominent candidate genes studied in the context of ND, because of their biological relevance as binding sites for nicotine. Until recently, most research on the role of nAChRs in ND has focused on two of these genes (encoding the a4-and b2-subunits) and not much attention has been paid to the possible contribution of the other nine brain nAChR subunit genes (a2-a3, a5-a7, a9-a10, b3-b4) to the pathophysiology and genetics of ND. This situation has changed dramatically in the last 2 years during which intensive research had addressed the issue, mainly from the genetics perspective, and has shown the importance of the CHRNA5-CHRNA3-CHRNB4 and CHRNA6-CHRNB3 loci in ND-related phenotypes. In this review, we highlight recent findings regarding the contribution of non-a4/b2-subunit containing nAChRs to ND, based on several lines of evidence: (1) human genetics studies (including linkage analysis, candidate-gene association studies and whole-genome association studies) of several ND-related phenotypes; (2) differential pharmacological and biochemical properties of receptors containing these subunits; (3) evidence from genetically manipulated mice; and (4) the contribution of nAChR genes to ND-related personality traits and neurocognitive profiles. Combining neurobiological genetic and behavioral perspectives, we suggest that genetic susceptibility to ND is not linked to one or two specific nAChR subtype genes but to several. In particular, the a3, a5-6 and b3-4 nAChR subunit-encoding genes may play a much more pivotal role in the neurobiology and genetics of ND than was appreciated earlier. At the functional level, variants in these subunit genes (most likely regulatory) may have independent as well as interactive contributions to the ND phenotype spectrum. We address methodological challenges in the field, highlight open questions and suggest possible pathways for future research.

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“…Most prominent among these are the human genetic association studies showing that single nucleotide polymorphisms in the gene cluster CHRNA5/Α3/Β4, encoding for the α3, α5, and β4 nAChR subunits, are closely associated with the risk for heavy smoking, inability to quit, and increased sensitivity to nicotine. [7][8][9][10][11] Further, studies in knockout mice show that the β4 nAChR subunit is necessary for nicotine withdrawal because withdrawal is greatly diminished in β4 null mice, but not in β2 null mice. 12,13 Unlike the wide distribution of α4β2 nAChR in the brain, the α3 and β4 subunits are expressed in a restricted number of brain areas, mainly the medial habenula and interpeduncular nucleus, major cholinergic tracts in the brain that have recently garnered increasing attention for their involvement in various aspects of nicotine dependence.…”

Section: Introductionmentioning

confidence: 99%

Functional Characterization of AT-1001, an α3β4 Nicotinic Acetylcholine Receptor Ligand, at Human α3β4 and α4β2 nAChR

Zaveri

Bertrand

Yasuda

et al. 2014

Nicotine &Amp; Tobacco Research

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Introduction: Genome-wide association studies linking the α3, β4, and α5 nicotinic acetylcholine receptor (nAChR) subunits to nicotine dependence suggest that α3β4* nAChR may be targets for smoking cessation pharmacotherapies. We previously reported that AT-1001, a selective α3β4* nAChR ligand binds with high affinity to rat α3β4 and human α3β4α5 nAChR, antagonizes epibatidine-induced activation of rat α3β4 nAChR in HEK cells and potently inhibits nicotine selfadministration in rats. Methods: Two-electrode voltage clamp was used for functional characterization of AT-1001 at recombinant human α3β4 and α4β2 nAChR expressed in Xenopus oocytes. Results: Concentration-response curves show that AT-1001 is a partial agonist at human α3β4 nAChR, evoking up to 35% of the maximal acetylcholine (ACh) response (50% effective concentration [EC 50 ] = 0.37 μM). AT-1001 showed very little agonist activity at the α4β2 nAChR, evoking only 6% of the ACh response (EC 50 = 1.5 μM). Pre-and co-application of various concentrations of AT-1001 with 50 μM ACh revealed a complex pattern of activation-inhibition by AT-1001 at α3β4 nAChR, which was best fitted by a 2-site equation. At α4β2 nAChR, co-exposure of AT-1001 with ACh only showed inhibition of ACh current with a shallower curve. Conclusions: AT-1001 is a partial agonist at the human α3β4 nAChR and causes desensitization at concentrations at which it evokes an inward current, resulting in an overall functional antagonism of α3β4 nAChR. AT-1001 does not significantly activate or desensitize α4β2 nAChR at the same concentrations as at the α3β4 nAChR, but does inhibit ACh responses at α4β2 nAChR at higher concentrations. A combination of these mechanisms may underlie the inhibition of nicotine selfadministration by AT-1001, suggesting that AT-1001 and compounds from this class may have clinical potential for smoking cessation pharmacotherapy.

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The CHRNA5/A3/B4 Gene Cluster Variability as an Important Determinant of Early Alcohol and Tobacco Initiation in Young Adults

Cited by 175 publications

References 48 publications

Genetic variability in nicotinic acetylcholine receptors and nicotine addiction: Converging evidence from human and animal research

Genetic variability in nicotinic acetylcholine receptors and nicotine addiction: Converging evidence from human and animal research

Differential contribution of genetic variation in multiple brain nicotinic cholinergic receptors to nicotine dependence: recent progress and emerging open questions

Functional Characterization of AT-1001, an α3β4 Nicotinic Acetylcholine Receptor Ligand, at Human α3β4 and α4β2 nAChR

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