Alternative titles; symbols
HGNC Approved Gene Symbol: CHRNB4
Cytogenetic location: 15q25.1 Genomic coordinates (GRCh38): 15:78,624,111-78,661,641 (from NCBI)
The nicotinic acetylcholine receptors (nAChRs) are members of a superfamily of ligand-gated ion channels that mediate fast signal transmission at synapses. The nAChRs are thought to be (hetero)pentamers composed of homologous subunits. See 118508 for additional background information on AChRs.
Tarroni et al. (1992) cloned a partial beta-4 subunit cDNA by screening a human neuroblastoma cDNA library with a rat beta-4 subunit probe. Using Northern blots and RT-PCR, Tarroni et al. (1992) found that the human beta-4 subunit is expressed as a 3.1-kb mRNA in neuroblastoma and small-cell lung carcinoma cell lines. Elliott et al. (1996) isolated a complete beta-4 clone from a neuroblastoma cell line cDNA library. The predicted 498-amino acid protein is 84% identical to rat beta-4 protein. They demonstrated that human beta-4 encoded a functional receptor when expressed in combination with alpha-2 (118502), alpha-3 (118503), or alpha-4 (118504) subunits in Xenopus oocytes. Groot Kormelink and Luyten (1997) also cloned a complete beta-4 cDNA from neuroblastoma cell line mRNA. On Northern blots of a neuroblastoma cell line, Groot Kormelink and Luyten (1997) found that the human beta-4 subunit is expressed as a 2.4-kb mRNA.
Transmitter-gated cation channels are detectors of excitatory chemical signals at synapses in the nervous system. Khakh et al. (2000) showed that structurally distinct alpha-3-beta-4 nicotinic and P2X(2) (600844) channels influence each other when coactivated. The activation of one channel type affects distinct kinetic and conductance states of the other, and coactivation results in nonadditive responses owing to inhibition of both channel types. State-dependent inhibition of nicotinic channels was revealed most clearly with mutant P2X(2) channels, and inhibition was decreased at lower densities of channel expression. In synaptically coupled myenteric neurons, nicotinic fast excitatory postsynaptic currents were occluded during activation of endogenously coexpressed P2X channels. Khakh et al. (2000) concluded that their data provide a molecular basis and a synaptic context for cross-inhibition between transmitter-gated channels.
Lou et al. (2007) reported a generalized MDR (GMDR) method that permitted adjustment for discrete and quantitative covariates and was applicable to both dichotomous and continuous phenotypes in population-based studies of various designs. They applied the method to a genetic study of 4 genes that were reported to be associated with nicotine dependence (188890): CHRNA2 (118502), CHRNB4, BDNF (113503), and NTRK2 (600456). They found significant joint action between CHRNB4 and NTRK2. Lou et al. (2007) commented that ubiquity of joint actions appears to be a natural property of complex inherited traits and that the term 'epistasis,' coined for a specific type of gene-by-gene interaction, has evolved to have different meanings in biologic and statistical genetics.
By using a combination of pharmacologic, molecular genetic, electrophysiologic, and feeding studies, Mineur et al. (2011) found that activation of hypothalamic alpha-3 (118503)-beta-4 nicotinic acetylcholine receptors leads to activation of proopiomelanocortin (POMC; 176830) neurons. POMC neurons and subsequent activation of melanocortin-4 receptors (MC4R; 155541) were critical for nicotinic-induced decreases in food intake in mice. The study of Mineur et al. (2011) demonstrated that nicotine decreases food intake and body weight by influencing the hypothalamic melanocortin system and identified critical molecular and synaptic mechanisms involved in nicotine-induced decreases in appetite.
Raimondi et al. (1992) mapped the CHRNA3 (118503), CHRNA5 (118505), and CHRNB4 genes to 15q24 by in situ hybridization and demonstrated that the 3 genes are physically linked.
Amos et al. (2008) placed the CHRNA3, CHRNA5, CHRNB4, and PSMA4 (176846) genes within a 100-kb region on chromosome 15q25.1.
For a discussion of an association between variation at the CHRNA3/CHRNA5/CHRNB4 gene cluster and susceptibility to smoking-related behavioral traits and lung cancer, see SQTL3 (612052).
Amos, C. I., Wu, X., Broderick, P., Gorlov, I. P., Gu, J., Eisen, T., Dong, Q., Zhang, Q., Gu, X., Vijayakrishnan, J., Sullivan, K., Matakidou, A., Wang, Y., Mills, G., Doheny, K., Tsai, Y.-Y., Chen, W. V., Shete, S., Spitz, M. R., Houlston, R. S. Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1. Nature Genet. 40: 616-622, 2008. [PubMed: 18385676] [Full Text: https://doi.org/10.1038/ng.109]
Elliott, K. J., Ellis, S. B., Berckhan, K. J., Urrutia, A., Chavez-Noriega, L. E., Johnson, E. C., Velicelebi, G., Harpold, M. M. Comparative structure of human neuronal alpha(2)-alpha(7) and beta(2)-beta(4) nicotinic acetylcholine receptor subunits and functional expression of the alpha(2), alpha(3), alpha(4), alpha(7), beta(2), and beta(4) subunits. J. Molec. Neurosci. 7: 217-228, 1996. [PubMed: 8906617] [Full Text: https://doi.org/10.1007/BF02736842]
Groot Kormelink, P. J., Luyten, W. H. M. L. Cloning and sequence of full-length cDNAs encoding the human neuronal nicotinic acetylcholine receptor (nAChR) subunits beta-3 and beta-4 and expression of seven nAChR subunits in the human neuroblastoma cell line SH-SY5Y and/or IMR-32. FEBS Lett. 400: 309-314, 1997. [PubMed: 9009220] [Full Text: https://doi.org/10.1016/s0014-5793(96)01383-x]
Khakh, B. S., Zhou, X., Sydes, J., Galligan, J. J., Lester, H. A. State-dependent cross-inhibition between transmitter-gated cation channels. Nature 406: 405-410, 2000. [PubMed: 10935636] [Full Text: https://doi.org/10.1038/35019066]
Lou, X.-Y., Chen, G.-B., Yan, L., Ma, J. Z., Zhu, J., Elston, R. C., Li, M. D. A generalized combinatorial approach for detecting gene-by-gene and gene-by-environment interactions with application to nicotine dependence. Am. J. Hum. Genet. 80: 1125-1137, 2007. [PubMed: 17503330] [Full Text: https://doi.org/10.1086/518312]
Mineur, Y. S., Abizaid, A., Rao, Y., Salas, R., DiLeone, R. J., Gundisch, D., Diano, S., De Biasi, M., Horvath, T. L., Gao, X.-B., Picciotto, M. R. Nicotine decreases food intake through activation of POMC neurons. Science 332: 1330-1332, 2011. [PubMed: 21659607] [Full Text: https://doi.org/10.1126/science.1201889]
Raimondi, E., Rubboli, F., Moralli, D., Chini, B., Fornasari, D., Tarroni, P., De Carli, L., Clementi, F. Chromosomal localization and physical linkage of the genes encoding the human alpha-3, alpha-5, and beta-4 neuronal nicotinic receptor subunits. Genomics 12: 849-850, 1992. [PubMed: 1572664] [Full Text: https://doi.org/10.1016/0888-7543(92)90324-l]
Tarroni, P., Rubboli, F., Chini, B., Zwart, R., Oortgiesen, M., Sher, E., Clementi, F. Neuronal-type nicotinic receptors in human neuroblastoma and small-cell lung carcinoma cell lines. FEBS Lett. 312: 66-70, 1992. [PubMed: 1330682] [Full Text: https://doi.org/10.1016/0014-5793(92)81411-e]