Alternative titles; symbols
HGNC Approved Gene Symbol: CHRM1
Cytogenetic location: 11q12.3 Genomic coordinates (GRCh38) : 11:62,908,679-62,921,878 (from NCBI)
Allard et al. (1987) determined that the CHRM1 gene encodes a predicted 460-amino acid protein that contains only 4 amino acid differences from the predicted sequence of the porcine CHRM1 protein. Hydropathicity analysis suggested that the receptor contains 7 membrane-spanning regions.
Goyal (1989) stated that 5 distinct but related muscarinic receptors had been identified, with apparent molecular masses ranging from 51,452 to 66,127 kD. These glycosylated proteins have single chains of 460 to 590 amino acids that are thought to span the plasma membrane 7 times, creating 4 extracellular domains, 7 helical hydrophobic transmembrane domains, and 4 intracellular domains. Each protein is the product of a different gene without introns in the coding sequence, and the amino acid sequences in the receptor subtypes are remarkably homologous among different animal species (Bonner et al., 1987; Peralta et al., 1987; Bonner et al., 1988; Liao et al., 1989). The nomenclature is confusing (Eglen and Whiting, 1986; Goyal, 1989). In structure and evolution, muscarinic receptors are distinct from their pharmacologic kin, the nicotinic receptors (see 100690, 100710, 100720, 100730).
Allard et al. (1987) determined that the CHRM1 gene contains 1 exon and spans 4.2 kb.
By means of analysis of somatic cell hybrids and by both isotopic and nonisotopic in situ hybridization, Bonner et al. (1991) assigned the CHRM1 gene to 11q12-q13.
Courseaux et al. (1996) used a combination of methods to refine maps of an approximately 5-Mb region of 11q13. They proposed the following gene order: cen--PGA--FTH1--UGB--AHNAK--ROM1--MDU1--CHRM1--COX8--EMK1--FKBP2--PLCB3--[PYGM, ZFM1]--FAU--CAPN1--[MLK3, RELA]--FOSL1--SEA--CFL1--tel.
Cholinergic modulation of hippocampal and cortical function plays an important role in memory and attention. The m1 muscarinic ACh receptor is abundant in the hippocampus and cerebral cortex. Using pharmacologic agents in rats, Marino et al. (1998) showed that the m1 receptor modulates NMDA receptor-meditated excitatory synaptic transmission in hippocampal CA1 pyramidal cells.
Dean et al. (2002) tested the hypothesis that muscarinic receptors are involved in the pathophysiology of schizophrenia by measuring CHRM1 and CHRM4 (118495) protein and mRNA as well as [3H]pirenzepine binding in Brodmann's area (BA) 9 and 40 obtained postmortem from 20 schizophrenic and 20 age/sex-matched control subjects. They observed a significant decrease in [3H]pirenzepine binding to BA 9 (p less than 0.02) but not BA 40 from subjects with schizophrenia. The level of CHRM1 protein (p less than 0.01) but not CHRM4 protein was decreased in BA 9 from schizophrenic subjects but neither protein was altered in BA 40. The level of CHRM1 mRNA was decreased in BA 9 (p less than 0.01) and BA 40 (p less than 0.01) from schizophrenic subjects, but CHRM4 mRNA was decreased only in BA 40 (p less than 0.005). Dean et al. (2002) interpreted the data as indicating that CHRM1 changes in the dorsolateral prefrontal cortex may have a role in the pathology of schizophrenia.
Seven-transmembrane receptor signaling is transduced by second messengers such as diacylglycerol (DAG) generated in response to the heterotrimeric guanine nucleotide-binding protein G(q) (600998) and is terminated by receptor desensitization and degradation of the second messengers. Nelson et al. (2007) showed that beta-arrestins (see 107940) coordinate both processes for the G(q)-coupled M1 muscarinic receptor (CHRM1). Beta-arrestins physically interact with diacylglycerol kinases (see 125855), enzymes that degrade DAG. Moreover, beta-arrestins are essential for conversion of DAG to phosphatidic acid after agonist stimulation, and this activity requires recruitment of the beta-arrestin-DGK complex to activated 7-transmembrane receptors. The dual function of beta-arrestins, limiting production of diacylglycerol (by receptor desensitization) while enhancing its rate of degradation, is analogous to their ability to recruit adenosine 3-prime,5-prime-monophosphate phosphodiesterases to G(s) (139320)-coupled beta-2-adrenergic receptors (ADRB2; 109690). Thus, Nelson et al. (2007) concluded that beta-arrestins can serve similar regulatory functions for disparate classes of 7-transmembrane receptors through structurally dissimilar enzymes that degrade chemically distinct second messengers.
Knox et al. (2010) hypothesized that parasympathetic innervation is required for epithelial progenitor cell function during organogenesis. Removal of the parasympathetic ganglion in mouse explant organ culture decreased the number and morphogenesis of keratin 5 (148040)-positive epithelial progenitor cells. These effects were rescued with an acetylcholine analog. Knox et al. (2010) demonstrated that acetylcholine signaling, via the muscarinic M1 receptor and epidermal growth factor receptor (131550), increased epithelial morphogenesis and proliferation of the keratin 5-positive progenitor cells. Parasympathetic innervation maintained the epithelial progenitor cell population in an undifferentiated state, which was required for organogenesis.
Anagnostaras et al. (2003) found that m1-null mice (m1 -/-) showed normal or enhanced memory for tasks that involved matching-to-sample problems and are hippocampus-dependent. In contrast, the null mice were severely impaired in non-matching-to-sample tasks, working memory, and consolidation, which require the hippocampus and the prefrontal cortex. The results suggested that the m1 receptor is involved in memory processes in which the cortex and hippocampus interact.
Using a CRISPR/Cas9 system, Niwa et al. (2018) created Chrm1 and Chrm3 (118494) knockout mice and found that these metabotropic cholinergic receptors have a crucial and redundant role in sleep. Chrm1 knockout mice had reduced duration of both rapid eye movement (REM) sleep and non-REM (NREM) sleep, demonstrating that Chrm1 has a role in regulating the duration of REM sleep but also contributes to the duration of NREM sleep. In contrast, Chrm3 knockout mice showed reduction of the duration of NREM sleep only. While the duration of REM sleep in Chrm3 knockout mice did not change, REM sleep became fragmented, demonstrating that Chrm3 has a role in regulating the duration of NREM sleep but also contributes to the consolidation of REM sleep. Furthermore, REM sleep was almost completely abolished in Chrm1 and Chrm3 double-knockout mice. Niwa et al. (2018) concluded that their findings provided evidence that cholinergic signaling is indeed essential for generating REM sleep.
Allard, W. J., Sigal, I. S., Dixon, R. A. F. Sequence of the gene encoding the human M1 muscarinic acetylcholine receptor. Nucleic Acids Res. 15: 10604 only, 1987. [PubMed: 3697105] [Full Text: https://doi.org/10.1093/nar/15.24.10604]
Anagnostaras, S. G., Murphy, G. G., Hamilton, S. E., Mitchell, S. L., Rahnama, N. P., Nathanson, N. M., Silva, A. J. Selective cognitive dysfunction in acetylcholine M1 muscarinic receptor mutant mice. Nature Neurosci. 6: 51-58, 2003. [PubMed: 12483218] [Full Text: https://doi.org/10.1038/nn992]
Bonner, T. I., Buckley, N. J., Young, A. C., Brann, M. R. Identification of a family of muscarinic acetylcholine receptor genes. Science 237: 527-532, 1987. Note: Erratum: Science 237: 1556 only, 1987. [PubMed: 3037705] [Full Text: https://doi.org/10.1126/science.3037705]
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., Young, A. C., Brann, M. R., Buckley, N. J. Cloning and expression of the human and rat m5 muscarinic acetylcholine genes. Neuron 1: 403-410, 1988. [PubMed: 3272174] [Full Text: https://doi.org/10.1016/0896-6273(88)90190-0]
Courseaux, A., Grosgeorge, J., Gaudray, P., Pannett, A. A. J., Forbes, S. A., Williamson, C., Bassett, D., Thakker, R. V., Teh, B. T., Farnebo, F., Shepherd, J., Skogseid, B., Larsson, C., Giraud, S., Zhang, C. X., Salandre, J., Calender, A. Definition of the minimal MEN1 candidate area based on a 5-Mb integrated map of proximal 11q13. Genomics 37: 354-365, 1996. [PubMed: 8938448]
Dean, B., McLeod, M., Keriakous, D., McKenzie, J., Scarr, E. Decreased muscarinic-1 receptors in the dorsolateral prefrontal cortex of subjects with schizophrenia. Molec. Psychiat. 7: 1083-1091, 2002. [PubMed: 12476323] [Full Text: https://doi.org/10.1038/sj.mp.4001199]
Eglen, R. M., Whiting, R. L. Muscarinic receptor subtypes: a critique of the current classification and a proposal for a working nomenclature. J. Auton. Pharm. 6: 323-346, 1986. [PubMed: 3546321] [Full Text: https://doi.org/10.1111/j.1474-8673.1986.tb00661.x]
Goyal, R. K. Muscarinic receptor subtypes: physiology and clinical implications. New Eng. J. Med. 321: 1022-1029, 1989. [PubMed: 2674717] [Full Text: https://doi.org/10.1056/NEJM198910123211506]
Knox, S. M., Lombaert, I. M. A., Reed, X., Vitale-Cross, L., Gutkind, J. S., Hoffman, M. P. Parasympathetic innervation maintains epithelial progenitor cells during salivary organogenesis. Science 329: 1645-1647, 2010. [PubMed: 20929848] [Full Text: https://doi.org/10.1126/science.1192046]
Liao, C. F., Themmen, A. P., Joho, R., Barberis, C., Birnbaumer, M., Birnbaumer, L. Molecular cloning and expression of a fifth muscarinic acetylcholine receptor. J. Biol. Chem. 264: 7328-7337, 1989. [PubMed: 2540186]
Marino, M. J., Rouse, S. T., Levey, A. I., Potter, L. T., Conn, P. J. Activation of the genetically defined m1 muscarinic receptor potentiates N-methyl-D-aspartate (NMDA) receptor currents in hippocampal pyramidal cells. Proc. Nat. Acad. Sci. 95: 11465-11470, 1998. [PubMed: 9736760] [Full Text: https://doi.org/10.1073/pnas.95.19.11465]
Nelson, C. D., Perry, S. J., Regier, D. S., Prescott, S. M., Topham, M. K., Lefkowitz, R. J. Targeting of diacylglycerol degradation to M1 muscarinic receptors by beta-arrestins. Science 315: 663-666, 2007. [PubMed: 17272726] [Full Text: https://doi.org/10.1126/science.1134562]
Niwa, Y., Kanda, G. N., Yamada, R. G., Shi, S., Sunagawa, G. A., Ukai-Tadenuma, M., Fujishima, H., Matsumoto, N., Masumoto, K., Nagano, M., Kasukawa, T., Galloway, J., Perrin, D., Shigeyoshi, Y., Ukai, H., Kiyonari, H., Sumiyama, K., Ueda, H. R. Muscarinic acetylcholine receptors Chrm1 and Chrm3 are essential for REM sleep. Cell Rep. 24: 2231-2247, 2018. [PubMed: 30157420] [Full Text: https://doi.org/10.1016/j.celrep.2018.07.082]
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]