CHRNA3

Neuronal acetylcholine receptor alpha subunit-3, also known as nAChRα3, is a protein encoded by the CHRNA3 gene in humans. The protein encoded by this gene is a subunit of certain nicotinic acetylcholine receptors (nAchR). The research on memethamine in animals shows that nAChR containing α-3 is related to the abuse and addiction of ethanol.

The CHRNA3 locus encodes a member of the nicotinic acetylcholine receptor protein family. The members of this protein family form a pentameric complex composed of α and β subunits. The encoded protein complex is a ligand-gated ion channel that may play a role in neurotransmission. The CHRNA3 gene encodes an alpha subunit, which contains characteristic adjacent cysteine residues. Clinical studies have shown that the polymorphism of this gene is related to the increased risk of smoking and increased sensitivity to lung cancer. In humans, the CHRNA3 gene is present on human chromosome 15, and CHRNA5, CHRNA3 and CHRNB4 are all present on this gene cluster, which together encode the subunits of the pentameric nicotinic acetylcholine receptor. Through the study of protein expression and distribution in vivo, it was found that CHRNA3 is mainly expressed in the adrenal gland, lymphatic tissue and retina, and it is locally enhanced in the human cerebellum.

CHRNA3 Expression Regulation

Studies have found that the environment is crucial for determining the proteins that regulate CHRNA3 expression, because genes have their own promoters and interacting enhancers, which can act in a tissue-dependent manner across the developmental time axis or in response to external disturbances. The specific protein (SP) family of transcription factors regulates the expression of all the genes, and each promoter has multiple SP binding sites. Unlike the tissue-specific expression of this subunit, the nearly universal expression of SP transcription factors strongly suggests that there are other proteins involved in regulating subunit expression. Human and rodent expression demonstrated tissue-specific regulation, for example, Pou3f1 and PHOX2A mediate CHRNA3 expression in neuronal cells, and Sox10 mediates CHRNA3 and CHRNB4 transcription in neuronal cells. Artemisinin induces CHRNA3 and CHRNB4 expression in trigeminal ganglia and neurons innervating the skin after inflammation.

Figure 1.The Genetic Locus CHRNA5–CHRNA3–CHRNB4 the Subunits of a Nicotinic Acetylcholine Receptor.(Glenda Lassi, et al.;2016)

Clinical Research of CHRNA3

There is evidence that there are risk factors in the 3'UTR of CHRNA3, which lead to nicotine dependence and smoking. Because smoking and alcohol abuse are often combined, the researchers studied this gene cluster to explore its impact on the risk of alcohol abuse. There is a gene cluster consisting of CHRNA5, CHRNA3, and CHRNB4 on chromosome 15, which encodes the subunit of the pentameric nicotinic acetylcholine receptor. At least two different (relatively independent) clusters of variation were found in this region related to nicotine dependence. One is a missense mutation of CHRNA5 that affects the function of the receptor, and the other is a change in the 3'untranslated region of CHRNA3. SNPs analysis studies found that there are both SNPs closely related to nicotine dependence and alcohol dependence in this gene cluster, and there are also SNPs that are closely related to alcohol dependence alone. This group of independent SNPs is related to differences in CHRNA5 expression levels, pointing out a potential mechanism of action.

References

1. Eng CM, et al.; Mapping of multiple subunits of the neuronal nicotinic acetylcholine receptor to chromosome 15 in man and chromosome 9 in mouse. Genomics. 1991, 9 (2): 278-82.
2. Sung-HaLee, et al.; Neuroscience of Nicotine: Mechanisms and Treatment. Chapter 43 - Nicotine Dependence and the CHRNA5/CHRNA3/CHRNB4. Academic Press. 2019, Pages 347-353.
3. Howard J.Edenberg. Biological Research on Addiction Comprehensive Addictive Behaviors and Disorders, Volume 2. Academic Press. 2013, Pages 499-508.
4. Glenda Lassi, et al.; The CHRNA5-A3-B4 Gene Cluster and Smoking: From Discovery to Therapeutics. Trends in Neurosciences. 2016, 39(12):851-861.