Alternative titles; symbols
HGNC Approved Gene Symbol: CHRM2
Cytogenetic location: 7q33 Genomic coordinates (GRCh38): 7:136,868,652-137,020,213 (from NCBI)
Using the porcine M2 sequence as probe, Peralta et al. (1987) cloned human CHRM2 from a genomic library. The deduced 466-amino acid protein shares structural features with other muscarinic receptors, including 7 transmembrane domains, an extracellular N terminus, and an intracellular C terminus. It also has 3 N-glycosylation sites at the N terminus. Northern blot analysis of rat tissues revealed expression in whole brain and in heart.
Zhou et al. (2001) determined that the CHRM2 gene contains 2 exons. A large intron resides in the 5-prime untranslated region. Analysis of the promoter region revealed no TATA box. The promoter contains an IRF2 (147576)-binding site and multiple C/EBP (116897) and OCT1 (164175) sites, as well as others.
Bonner (1990) indicated that the CHRM2 gene maps to chromosome 7q35-q36 by in situ hybridization (Bonner et al., 1991). Badner et al. (1995) mapped the gene to 7q31-q35 by multipoint linkage analysis.
Stumpf (2020) mapped the CHRM2 gene to chromosome 7q33 based on an alignment of the CHRM2 sequence (GenBank BC106742) with the genomic sequence (GRCh38).
Crystal Structure
Haga et al. (2012) reported the structure of the antagonist-bound human M2 muscarinic acetylcholine receptor. The antagonist 3-quinuclidinyl-benzilate binds in the middle of a long aqueous channel extending approximately two-thirds through the membrane. The orthosteric binding pocket is formed by amino acids that are identical in all 5 muscarinic receptor subtypes, and shares structural homology with other functionally unrelated acetylcholine binding proteins from different species. A layer of tyrosine residues forms an aromatic cap restricting dissociation of the bound ligand. A binding site for allosteric ligands has been mapped to residues at the entrance to the binding pocket near this aromatic cap. Haga et al. (2012) concluded that the structure of the M2 receptor provides insights into the challenges of developing subtype-selective ligands for muscarinic receptors and their propensity for allosteric regulation.
Cryoelectron Microscopy
Staus et al. (2020) presented a cryoelectron microscopy structure of beta-arrestin-1 (107940) in complex with M2 muscarinic receptor (M2R) reconstituted in lipid nanodiscs. The M2R-beta-arrestin-1 complex displays a multimodal network of flexible interactions, including binding of the N domain of beta-arrestin-1 to phosphorylated receptor residues and insertion of the finger loop of beta-arrestin-1 into the M2R 7-transmembrane bundle, which adopts a conformation similar to that in the M2R-heterotrimeric Go protein (GNAO1; 139311) complex. Moreover, the cryoelectron microscopy map revealed that the C-edge of beta-arrestin-1 engages the lipid bilayer. Through atomistic simulations and biophysical, biochemical, and cellular assays, Staus et al. (2020) showed that the C-edge is critical for stable complex formation, beta-arrestin-1 recruitment, receptor internalization, and desensitization of G protein activation. Staus et al. (2020) concluded that their data suggested that the cooperative interactions of beta-arrestin with both the receptor and the phospholipid bilayer contribute to its functional versatility.
Wang et al. (2004) examined 11 SNPs within and flanking the CHRM2 gene in 262 families with alcohol dependence from the Collaborative Study on the Genetics of Alcoholism (COGA). Three SNPs showed highly significant association with alcoholism (103780) (p = 0.004, 0.007, and 0.007, respectively). Two SNPs were significantly associated with major depressive syndrome (MDD; 608516) (p = 0.004 and 0.017). Haplotype analyses revealed that the most common haplotype, T-T-T (rs1824024, rs2061174, and rs324650), was undertransmitted to affected individuals with alcohol dependence and major depressive syndrome.
Luo et al. (2005) examined the relationships between variation in the CHRM2 gene and alcohol dependence (AD), drug dependence (DD), and affective disorders, using a novel extended case-control structured association method. Six markers at CHRM2 and 38 ancestry-informative markers were genotyped in a sample of 871 subjects, including 333 healthy controls and 538 AD and/or DD subjects (415 with AD and 346 with DD). The same CHRM2 markers were genotyped in a sample of 137 subjects with affective disorders. All 6 markers were in Hardy-Weinberg equilibrium in controls, but rs1824024 was in Hardy-Weinberg disequilibrium in the AD and DD groups. Regression analysis identified specific alleles, genotypes, haplotypes, and diplotypes that were significantly associated with risk for each disorder. Luo et al. (2005) concluded that variation in the CHRM2 gene may predispose to alcohol dependence, drug dependence, and affective disorders.
In a large, adequately powered, clinical depression case-control sample (1,420 cases and 1,624 controls), Cohen-Woods et al. (2009) found no association between previously implicated SNPs in the CHRM2 gene and major depression.
Badner, J. A., Yoon, S. W., Turner, G., Bonner, T. I., Detera-Wadleigh, S. D. Multipoint genetic linkage analysis of the m2 human muscarinic receptor gene. Mammalian Genome 6: 489-490, 1995. [PubMed: 7579899] [Full Text: https://doi.org/10.1007/BF00360666]
Bonner, T. I., Modi, W. S., Seuanez, H. N., O'Brien, S. J. Chromosomal mapping of five human genes encoding muscarinic acetylcholine receptors. (Abstract) Cytogenet. Cell Genet. 58: 1850-1851, 1991.
Bonner, T. I. Personal Communication. Bethesda, Md. 9/21/1990.
Cohen-Woods, S., Gaysina, D., Craddock, N., Farmer, A., Gray, J., Gunasinghe, C., Hoda, F., Jones, L., Knight, J., Korszun, A., Owen, M. J., Sterne, A., Craig, I. W., McGuffin, P. Depression case control (DeCC) study fails to support involvement of the muscarinic acetylcholine receptor M2 (CHRM2) gene in recurrent major depressive disorder. Hum. Molec. Genet. 18: 1504-1509, 2009. [PubMed: 19181679] [Full Text: https://doi.org/10.1093/hmg/ddp051]
Haga, K., Kruse, A. C., Asada, H., Yurugi-Kobayashi, T., Shiroishi, M., Zhang, C., Weis, W. I., Okada, T., Kobilka, B. K., Haga, T., Kobayashi, T. Structure of the human M2 muscarinic acetylcholine receptor bound to an antagonist. Nature 482: 547-551, 2012. [PubMed: 22278061] [Full Text: https://doi.org/10.1038/nature10753]
Luo, X., Kranzler, H. R., Zuo, L., Wang, S., Blumberg, H. P., Gelernter, J. CHRM2 gene predisposes to alcohol dependence, drug dependence and affective disorders: results from an extended case-control structured association study. Hum. Molec. Genet. 14: 2421-2434, 2005. [PubMed: 16000316] [Full Text: https://doi.org/10.1093/hmg/ddi244]
Peralta, E. G., Ashkenazi, A., Winslow, J. W., Smith, D. H., Ramachandran, J., Capon, D. J. Distinct primary structures, ligand-binding properties and tissue-specific expression of four human muscarinic acetylcholine receptors. EMBO J. 6: 3923-3929, 1987. [PubMed: 3443095] [Full Text: https://doi.org/10.1002/j.1460-2075.1987.tb02733.x]
Staus, D. P., Hu, H., Robertson, M. J., Kleinhenz, A. L. W., Wingler, L. M., Capel, W. D., Latorraca, N. R., Lefkowitz, R. J., Skiniotis, G. Structure of the M2 muscarinic receptor-beta-arrestin complex in a lipid nanodisc. Nature 579: 297-302, 2020. [PubMed: 31945772] [Full Text: https://doi.org/10.1038/s41586-020-1954-0]
Stumpf, A. M. Personal Communication. Baltimore, Md. 06/30/2020.
Wang, J. C., Hinrichs, A. L., Stock, H., Budde, J., Allen, R., Bertelsen, S., Kwon, J. M., Wu, W., Dick, D. M., Rice, J., Jones, K., Nurnberger, J. I., Jr., and 10 others. Evidence of common and specific genetic effects: association of the muscarinic acetylcholine receptor M2 (CHRM2) gene with alcohol dependence and major depressive syndrome. Hum. Molec. Genet. 13: 1903-1911, 2004. [PubMed: 15229186] [Full Text: https://doi.org/10.1093/hmg/ddh194]
Zhou, C., Fryer, A. D., Jacoby, D. B. Structure of the human M(2) muscarinic acetylcholine receptor gene and its promoter. Gene 271: 87-92, 2001. [PubMed: 11410369] [Full Text: https://doi.org/10.1016/s0378-1119(01)00494-2]