Alternative titles; symbols
HGNC Approved Gene Symbol: CHRNA7
Cytogenetic location: 15q13.3 Genomic coordinates (GRCh38): 15:32,030,483-32,173,018 (from NCBI)
Doucette-Stamm et al. (1993) isolated the human alpha-7 subunit by screening a human fetal brain cDNA library with a rat alpha-7 probe. Independently, Peng et al. (1994) isolated an alpha-7 clone, and found that it was expressed as 3 mRNAs of 5.9, 2.6 and 1.3 kb on Northern blots of a neuroblastoma cell line. The human alpha-7 subunit assembled into functional homomers when expressed in Xenopus oocytes.
Chini et al. (1994) isolated cDNA and genomic clones coding for the human alpha-7 neuronal nicotinic receptor subunit, the major component of brain nicotinic receptors that are blocked by alpha-bungarotoxin. The CHRNA7 cDNA encodes a mature protein of 479 amino acids that is highly homologous to the rat alpha-7 neuronal nicotinic subunit (90%). Elliott et al. (1996) and Groot Kormelink and Luyten (1997) also cloned the alpha-7 gene and noted differences with the sequence reported by Peng et al. (1994). By Northern blot analysis, Groot Kormelink and Luyten (1997) found 3 alpha-7 mRNAs (5.7, 3.1 and 1.9 kb) expressed in a neuroblastoma cell line.
Gault et al. (1998) provided a diagram of the CHRNA7 protein structure. CHRNA7 has a signal peptide, followed by an N-terminal extracellular domain, 3 membrane-spanning regions, an intracellular domain, a fourth transmembrane region, and an extracellular C-terminal tail. The N-terminal domain has 3 glycosylation sites, and the intracellular domain has 3 putative phosphorylation sites. PCR amplification from normal human brain revealed 6 different CHRNA7 transcripts generated by alternative splicing of exons 3 through 5.
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. Doucette-Stamm et al. (1993) stated that alpha-7, unlike other neuronal nAChR subunits, forms a homooligomeric channel, displays marked permeability to calcium ions, and is highly sensitive to alpha-bungarotoxin when expressed in Xenopus oocytes. See 118508 for additional background information on AChRs.
Excessive inflammation and tumor necrosis factor (TNF; 191160) synthesis cause morbidity and mortality in diverse human diseases including endotoxemia, sepsis, rheumatoid arthritis (180300), and inflammatory bowel disease (see 266600). Highly conserved, endogenous mechanisms normally regulate the magnitude of innate immune responses and prevent excessive inflammation. The nervous system, through the vagus nerve, can inhibit significantly and rapidly the release of macrophage TNF and attenuate systemic inflammatory responses. Wang et al. (2003) demonstrated that the nicotinic acetylcholine receptor alpha-7 subunit is required for acetylcholine inhibition of macrophage TNF release. Electrical stimulation of the vagus nerve inhibited TNF synthesis in wildtype mice, but failed to inhibit TNF synthesis in alpha-7-deficient mice. Thus, Wang et al. (2003) concluded that the nicotinic acetylcholine receptor alpha-7 subunit is essential for inhibiting cytokine synthesis by the cholinergic antiinflammatory pathway.
Counts et al. (2007) found a 60% increase in CHRNA7 mRNA levels in cholinergic neurons of the nucleus basalis in patients with mild to moderate Alzheimer disease (AD; 104300) compared to those with mild cognitive impairment or normal controls. Expression levels of CHRNA7 were inversely associated with cognitive test scores. Counts et al. (2007) suggested that upregulation of CHRNA7 receptors may be a compensatory response to maintain basocortical cholinergic activity during disease progression or may act with beta-amyloid (APP; 104760) in disease pathogenesis.
Gault et al. (1998) determined that the CHRNA7 gene contains 10 exons and spans more than 75 kb. The 5-prime flanking region is 77% GC rich and lacks a consensus TATA box sequence. It has consensus binding sites for SP1 (189906), AP2 (see 107580), EGR1 (128990), and CREB (CREB1; 123810).
By fluorescence in situ hybridization, Chini et al. (1994) mapped the CHRNA7 gene to 15q14, a region frequently rearranged in patients carrying a bisatellite chromosome 15 with a large inverted duplication (Wisniewski et al., 1979). This chromosomal aberration is associated with mental retardation and with epileptic crises, which are sometimes resistant to therapy. Since the number of alpha-bungarotoxin binding sites, mainly composed of alpha-7 subunits, is related to seizure sensitivity in a mouse strain, Chini et al. (1994) suggested a role for the CHRNA7 gene in the epileptic seizures of these patients. Three other nicotinic receptor subunit genes are located on chromosome 15; the alpha-3 (CHRNA3; 118503), alpha-5 (CHRNA5; 118505), and beta-4 (CHRNB4; 118509) genes are clustered on band 15q24.
By fluorescence in situ hybridization, Orr-Urtreger et al. (1995) confirmed the assignment of this gene to 15q13-q14. They had previously mapped the mouse homolog (symbolized Acra7) to a homologous region on chromosome 7 by analyzing a panel of DNA samples from an interspecific backcross.
Linkage to Schizophrenia
For discussion of a possible association between the CHRNA7 gene and susceptibility to schizophrenia, see SCZD13 (613025).
Linkage to Epilepsy
For discussion of a possible association between the CHRNA7 gene an epilepsy, see idiopathic generalized epilepsy 7 (EIG7; 604827).
See also 612001 for a description of a 15q13.3 microdeletion syndrome, including the deletion of CHRNA7, associated with mental retardation and seizures.
CHRNA7 has been implicated in various human psychiatric and behavioral disorders. Using 12 behavioral assessments and electroencephalogram recordings with freely-moving mice, Yin et al. (2017) found that loss of Chrna7 expression was not sufficient to cause statistically significant social, behavioral, or neuropsychiatric-like changes. Yin et al. (2017) also found no evidence for electrophysiologic phenotypic difference between Chrna7 -/- and wildtype mice. They concluded that knockout of Chrna7 in mice does not recapitulate phenotypes observed in humans with chromosome 15q13.3 microdeletion syndrome.
Chini, B., Raimond, E., Elgoyhen, A. B., Moralli, D., Balzaretti, M., Heinemann, S. Molecular cloning and chromosomal localization of the human alpha-7-nicotinic receptor subunit gene (CHRNA7). Genomics 19: 379-381, 1994. [PubMed: 8188270] [Full Text: https://doi.org/10.1006/geno.1994.1075]
Counts, S. E., He, B., Che, S., Ikonomovic, M. D., DeKosky, S. T., Ginsberg, S. D., Mufson, E. J. Alpha-7 nicotinic receptor up-regulation in cholinergic basal forebrain neurons in Alzheimer disease. Arch. Neurol. 64: 1771-1776, 2007. [PubMed: 18071042] [Full Text: https://doi.org/10.1001/archneur.64.12.1771]
Doucette-Stamm, L., Monteggia, L. M., Donnelly-Roberts, D., Wang, M. T., Lee, J., Tian, J., Giordano, T. Cloning and sequence of the human alpha-7 nicotinic acetylcholine receptor. Drug Dev. Res. 30: 252-256, 1993.
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]
Gault, J., Robinson, M., Berger, R., Drebing, C., Logel, J., Hopkins, J., Moore, T., Jacobs, S., Meriwether, J., Choi, M. J., Kim, E. J., Walton, K., Buiting, K., Davis, A., Breese, C., Freedman, R., Leonard, S. Genomic organization and partial duplication of the human alpha-7 neuronal nicotinic acetylcholine receptor gene (CHRNA7). Genomics 52: 173-185, 1998. [PubMed: 9782083] [Full Text: https://doi.org/10.1006/geno.1998.5363]
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]
Orr-Urtreger, A., Seldin, M. F., Baldini, A., Beaudet, A. L. Cloning and mapping of the mouse alpha-7-neuronal nicotinic acetylcholine receptor. Genomics 26: 399-402, 1995. [PubMed: 7601470] [Full Text: https://doi.org/10.1016/0888-7543(95)80228-e]
Peng, X., Katz, M., Gerzanich, V., Anand, R., Lindstrom, J. Human alpha-7 acetylcholine receptor: cloning of the alpha-7 subunit from the SH-SY5Y cell line and determination of pharmacological properties of native receptors and functional alpha-7 homomers expressed in Xenopus oocytes. Molec. Pharm. 45: 546-554, 1994. [PubMed: 8145738]
Wang, H., Yu, M., Ochani, M., Amella, C. A., Tanovic, M., Susarla, S., Li, J. H., Wang, H., Yang, H., Ulloa, L., Al-Abed, Y., Czura, C. J., Tracey, K. J. Nicotinic acetylcholine receptor alpha-7 subunit is an essential regulator of inflammation. Nature 421: 384-388, 2003. [PubMed: 12508119] [Full Text: https://doi.org/10.1038/nature01339]
Wisniewski, L., Hassold, T., Heffelfinger, J., Higgins, J. V. Cytogenetic and clinical studies in five cases of inv dup (15). Hum. Genet. 50: 259-270, 1979. [PubMed: 489010] [Full Text: https://doi.org/10.1007/BF00399391]
Yin, J., Chen, W., Yang, H., Xue, M., Schaaf, C. P. Chrna7 deficient mice manifest no consistent neuropsychiatric and behavioral phenotypes. Sci. Rep. 7: 39941, 2017. Note: Electronic Article. [PubMed: 28045139] [Full Text: https://doi.org/10.1038/srep39941]