Neuronal Nicotinic Receptor Subunit Genes Research Articles

Association of the CHRNA4 Neuronal Nicotinic Receptor Subunit Gene with Frequency of Binge Drinking in Young Adults

Binge drinking is responsible for over half of all alcohol-related deaths and results in significant health and economic costs to individuals and society. Knowledge of genetic aspects of this behavior, particularly as it emerges in young adulthood, could lead to improved treatment and prevention programs. We have focused on the association of variation in neuronal nicotinic receptor subunit genes (CHRNs) in a cohort of 702 Hispanic and non-Hispanic White young adults who are part of the Social and Emotional Contexts of Adolescent Smoking Patterns (SECASP) study. Fifty-five single nucleotide polymorphisms (SNPs) covering the variation in 5 CHRNs (CHRNA4, CHRNB2, CHRNA2, CHRNB3A6, and CHRNA5A3B4) were studied. Frequency of binge drinking and other correlated alcohol consumption measures were significantly associated with SNPs in CHRNA4 (p-values ranged from 0.0003 to 0.02), but not with SNPs in other CHRNs. This association was independent of smoking status in our cohort. Variants in CHRNA4 may contribute to risk of binge drinking in young adults in this cohort. Results will need to be confirmed in independent samples.

The neuronal nicotinic receptor subunit genes (CHRNA6 and CHRNB3) are associated with subjective responses to tobacco

Neuronal nicotinic acetylcholine receptors have been implicated in various measures of nicotine dependence. In this paper, we present findings from an exploratory study of single nucleotide polymorphisms (SNPs) in the CHRNB3 and CHRNA6 genes with tobacco and alcohol phenotypes, including frequency of use and three subjective response factors occurring shortly after initiation of use. Subjects were 1056 ethnically diverse adolescents ascertained from clinical and community settings. The most significant associations were found between two CHRNB3 SNPs (rs4950 and rs13280604) and the three subjective response factors to initial tobacco use. These findings were replicated in a separate community sample of 1524 families participating in the National Longitudinal Study of Adolescent Health. Both CHRNB3 SNPs were found to be associated with similar measures of subjective response to tobacco. These results indicate that early subjective response to nicotine may be a valuable endophenotype for genetic studies aimed at uncovering genes contributing to nicotine use and addiction.

Association of the neuronal nicotinic receptor β2 subunit gene (CHRNB2) with subjective responses to alcohol and nicotine

Nicotine addiction and alcohol dependence are highly comorbid disorders that are likely to share overlapping genetic components. We have examined two neuronal nicotinic receptor subunit genes (CHRNA4 and CHRNB2) for possible associations with nicotine and alcohol phenotypes, including measures of frequency of use and measures of initial subjective response in the period shortly after first using the drugs. The subjects were 1,068 ethnically diverse young adults participating in ongoing longitudinal studies of adolescent drug behaviors at the University of Colorado, representing both clinical and community samples. Analysis of six SNPs in the CHRNA4 gene provided modest support for an association with past 6 month use of alcohol in Caucasians (three SNPs with P < 0.08), but no evidence for an association with tobacco and CHRNA4 was detected. However, a SNP (rs2072658) located immediately upstream of CHRNB2 was associated with the initial subjective response to both alcohol and tobacco. This study provides the first evidence for association between the CHRNB2 gene and nicotine- and alcohol-related phenotypes, and suggests that polymorphisms in CHRNB2 may be important in mediating early responses to nicotine and alcohol.

Identification of molecular variants at the promoter region of the human α7 neuronal nicotinic acetylcholine receptor subunit gene but lack of association with schizophrenia

The human α7 neuronal nicotinic receptor subunit gene has been considered as a candidate gene for P50 sensory gating deficit in schizophrenic patients. Because P50 sensory gating deficit is a common neurophysiological dysfunction in patients with schizophrenia and schizophrenia spectrum disorders, it is conceivable to hypothesize that the human α7 neuronal nicotinic receptor subunit gene might be a susceptible gene for schizophrenia. Researchers have reported that mutations in the protein-coding sequences of the human α7 neuronal nicotinic receptor subunit gene are very rare. Therefore, we searched for mutations at the promoter region of the human α7 neuronal nicotinic receptor subunit gene and performed a genetic association study in 249 unrelated Han Chinese schizophrenic patients and 273 non-psychotic subjects from Taiwan. Two molecular variants were identified and designated g.−213G>A and g.−324A>G, respectively. The g.−213G>A variant was found to obliterate a putative NF-1 transcription factor binding site using computer analysis. One out of 249 patients was detected to be a heterozygote for this variant, but none of 273 control subjects was. The g.−324A>G variant was also very rare in both patients and control subjects, only one heterozygote of this variant was identified in 249 patients and 273 control subjects, respectively. Hence, in this study, we did not find mutations in the human α7 neuronal nicotinic receptor subunit gene that are associated with schizophrenia in our population.

Regulation of Transcription in the Neuronal Nicotinic Receptor Subunit Gene Cluster by a Neuron-selective Enhancer and ETS Domain Factors

Expression of neurotransmitter receptors encoded by the nicotinic acetylcholine receptor (nAchR) subunit gene cluster depends on coexpression of the beta4, alpha3, and alpha5 subunits in certain kinds of neurons. One way in which coexpression might be achieved is through the regulation of promoters in the cluster by neuron-selective enhancers. The beta43' enhancer is located between the beta4 and alpha3 promoters and it directs cell type-specific expression in cell lines. It is not known, however, whether beta43' is active in neurons. Therefore, we assayed beta43' in dissociated rat sympathetic ganglia cultures, which contain nAchR-positive neurons as well as nAchR-negative non-neuronal cells. Reporters controlled by the alpha3 promoter and beta43' were expressed in a neuron-selective manner; greater than 90% and up to 100% of luciferase expression was detected in neurons. Neuron selectivity was maintained when beta43' was placed next to ubiquitously active viral promoters. In contrast, replacing beta43' with the SV40 enhancer eliminated neuron selectivity. The enhancer is composed of at least two separate but functionally interdependent elements, each of which interacts with a different type of ETS domain factor. These findings support a model in which beta43' controls neuronal expression of one or more genes in the cluster through interactions with a combination of ETS factors.

Neuronal Nicotinic Receptor Expression in Sensory Neurons of the Rat Trigeminal Ganglion: Demonstration of α3β4, a Novel Subtype in the Mammalian Nervous System

The identification of a family of neuronal nicotinic receptor subunit genes establishes the potential for multiple subtypes with diverse physiological functions. Virtually all of the high affinity nicotinic receptors measured to date in the rodent CNS are composed of alpha4 and beta2 subunits only. However, the demonstration of other subunit transcripts in a variety of central and peripheral nervous tissues suggests a greater degree of receptor subtype heterogeneity than so far has been elucidated. The purpose of the present studies was to determine at the mRNA and protein levels which neuronal nicotinic receptor subunits are expressed by sensory neurons of the rat trigeminal ganglion and in what combinations these gene products associate to form neuronal nicotinic receptor subtypes in this tissue. Radioreceptor binding analysis indicated that in the adult rat trigeminal ganglion there exist at least two nicotinic receptor binding sites with differing affinities for [3H]-epibatidine. In situ hybridization histochemical studies revealed the existence of mRNA encoding the alpha3, alpha4, alpha5, beta2, and beta4 subunits, but not the alpha2 subunit. Immunoprecipitation with subunit-specific antisera demonstrated that each of the subunits present in the ganglion at the mRNA level is a constituent of nicotinic receptors capable of binding 3H-epibatidine. Various applications of these approaches yielded strong evidence that, in addition to alpha4beta2, which is thought to be the predominant neuronal nicotinic receptor subtype in the rodent CNS, trigeminal sensory neurons express as the principal subtype alpha3beta4, which has not been demonstrated previously in mammalian nervous tissue.