Chrna3, encoding the Alpha-3 subunit of the nicotinic acetylcholine receptor (nAChR), is crucial for fast synaptic transmission in the autonomic ganglia. nAChRs are allosterically regulated, ligand-gated ion channels involved in many neural functions, and the Chrna3-containing nAChRs contribute to the overall function of this receptor family [1,5].

Genetic variation in the CHRNA5-CHRNA3-CHRNB4 gene cluster has been associated with increased vulnerability to tobacco dependence, smoking-associated diseases like lung cancer, and chronic obstructive pulmonary disease (COPD) [1,3,6,9]. In a Mexican population, the A allele of the CHRNA3 rs1051730 polymorphism was associated with heavy smoking, as well as an increased risk of lung cancer and COPD [3]. In the Chinese Han population, a CHRNA3 variant was linked to an increased risk of lung adenocarcinoma, especially in female nonsmokers [6]. In the Korean population, a CHRNA3 SNP was associated with COPD [9]. Additionally, specific CHRNA3 polymorphisms are associated with nicotine addiction in humans, and novel haplotypes in CHRNA3 were found to be associated with nicotine addiction [4]. In knockout mouse models, the α5 nAChR subunits (encoded by CHRNA5 in the same gene cluster) in the habenula-interpeduncular nucleus pathway have been highlighted in regulating nicotine intake, which may also imply a role of Chrna3-containing nAChRs in this process [2]. Rare pathologic variants in CHRNA3 have been found in patients with familial autonomic ganglionopathy presenting with severe neurogenic orthostatic hypotension, small nonreactive pupils, and constipation [5]. A patient with neurogenic bladder, vesicoureteral reflux, mydriasis, and gastrointestinal dysmotility was found to have novel compound heterozygous variants in CHRNA3 [7]. Also, the rs1051730 genotype in CHRNA3 was associated with short-term smoking cessation in treatment-seeking smokers in the UK [8].

In conclusion, Chrna3 is essential for autonomic ganglia synaptic transmission. Studies, especially those using genetic models like mouse knockouts, have revealed its significant associations with nicotine-related addictions, smoking-associated diseases such as lung cancer and COPD, and certain autonomic disorders. Understanding Chrna3's function provides insights into the mechanisms of these diseases and potential targets for treatment.

References:

1. Picciotto, Marina R, Kenny, Paul J. 2021. Mechanisms of Nicotine Addiction. In Cold Spring Harbor perspectives in medicine, 11, . doi:10.1101/cshperspect.a039610. https://pubmed.ncbi.nlm.nih.gov/32341069/

2. Ware, Jennifer J, van den Bree, Marianne, Munafò, Marcus R. 2012. From men to mice: CHRNA5/CHRNA3, smoking behavior and disease. In Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco, 14, 1291-9. doi:10.1093/ntr/nts106. https://pubmed.ncbi.nlm.nih.gov/22544838/

3. Pérez-Morales, Rebeca, González-Zamora, Alberto, González-Delgado, María Fernanda, Martínez-Ramírez, Ollin Celeste, Rubio, Julieta. 2018. CHRNA3 rs1051730 and CHRNA5 rs16969968 polymorphisms are associated with heavy smoking, lung cancer, and chronic obstructive pulmonary disease in a mexican population. In Annals of human genetics, 82, 415-424. doi:10.1111/ahg.12264. https://pubmed.ncbi.nlm.nih.gov/29993116/

4. Chmielowiec, Krzysztof, Chmielowiec, Jolanta, Strońska-Pluta, Aleksandra, Jaroń, Aleksandra, Grzywacz, Anna. 2022. Association of Polymorphism CHRNA5 and CHRNA3 Gene in People Addicted to Nicotine. In International journal of environmental research and public health, 19, . doi:10.3390/ijerph191710478. https://pubmed.ncbi.nlm.nih.gov/36078193/

5. Shibao, Cyndya A, Joos, Karen, Phillips, John A, Roberston, David, Biaggioni, Italo. 2021. Familial Autonomic Ganglionopathy Caused by Rare CHRNA3 Genetic Variants. In Neurology, 97, e145-e155. doi:10.1212/WNL.0000000000012143. https://pubmed.ncbi.nlm.nih.gov/33947782/

6. He, Ping, Yang, Xue-Xi, He, Xuan-Qiu, Yao, Guang-Yu, He, Jian-Xing. 2014. CHRNA3 polymorphism modifies lung adenocarcinoma risk in the Chinese Han population. In International journal of molecular sciences, 15, 5446-57. doi:10.3390/ijms15045446. https://pubmed.ncbi.nlm.nih.gov/24686516/

7. Anand, Asha, Hildebrandt, Clara C, Shenoy, Vivek, Sutherland, Richard W. 2024. Novel CHRNA3 variants identified in a patient with bladder dysfunction, dysautonomia, and gastrointestinal dysmotility. In American journal of medical genetics. Part A, 194, e63526. doi:10.1002/ajmg.a.63526. https://pubmed.ncbi.nlm.nih.gov/38192228/

8. Munafò, Marcus R, Johnstone, Elaine C, Walther, Donna, Murphy, Michael F G, Aveyard, Paul. 2011. CHRNA3 rs1051730 genotype and short-term smoking cessation. In Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco, 13, 982-8. doi:10.1093/ntr/ntr106. https://pubmed.ncbi.nlm.nih.gov/21690317/

9. Kim, Woo Jin, Oh, Yeon-Mok, Kim, Tae-Hyung, Lim, Seong-Yong, Lee, Sang Do. 2012. CHRNA3 variant for lung cancer is associated with chronic obstructive pulmonary disease in Korea. In Respiration; international review of thoracic diseases, 86, 117-22. doi:10.1159/000342976. https://pubmed.ncbi.nlm.nih.gov/23207642/