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CHRM1  -  cholinergic receptor, muscarinic 1

Homo sapiens

Synonyms: HM1, M1, M1R, Muscarinic acetylcholine receptor M1
 
 
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Disease relevance of CHRM1

  • Positive antibodies to CHRM1 were found in 34.1%, 34.9%, 33.3%, and 9.1% of patients with schizophrenic disorders (n=44), mood disorders (n=63), other psychiatric disorders (n=15) and autoimmune diseases (n=33), respectively [1].
  • The patients with positive autoantibodies to CHRM1 had a significantly higher mean score (1.81) of 'feeling of muscle weakness' than negative patients (1.18) among CFS patients (p<0.01) [2].
  • These results are the first demonstration that M1 and M2 mAChRs undergo sequestration following transient hypoxia [3].
  • METHODS: We applied the phenotypic screening process to an analysis of the m1 muscarinic acetylcholine receptor (CHRM1) gene in a cohort of 74 individuals, including 48 diagnosed with neurodegenerative disease, primarily Alzheimer disease, who have been stratified according to their clinical response to the acetylcholinesterase inhibitor donepezil [4].
  • On the other hand, ziprasidone's low affinity for alpha1-adrenoceptors, as well as histamine H1 and muscarinic M1 receptors, suggests that patients should experience relatively little orthostatic hypotension, sedation, cognitive disturbance, weight gain, or dysregulation of prolactin levels [5].
 

Psychiatry related information on CHRM1

  • The results of the current study suggest that elucidation of the mechanism or mechanisms of interaction of xanomeline with the M1 mAChR is particularly important in relation to the potential therapeutic use of this agent in the treatment of Alzheimer's disease [6].
  • CONCLUSION: The results confirm that the m1 receptor gene (CHRM1) is not highly polymorphic in the human population, suggesting that genetic variation within the coding exon of this gene is not a contributing factor to the clinical variability observed during treatment of dementia with cholinergic enhancement therapies [4].
  • Because of uncertainties about the pharmacological specificity of biperiden, further studies are needed to determine the mechanism of action and the role of M1 receptors subtypes in the regulation of REM sleep [7].
  • In the temporal cortex, there was a smaller proportion of M1 receptors in atypical Pick's disease than in the controls or in the patients with Alzheimer's disease and dementia with Lewy bodies [8].
  • The patients underwent ADAS-COG psychometric assessment and SPECT brain imaging with (123)I quinuclidinyl benzilate (QNB), to demonstrate the postsynaptic muscarinic M1 receptor, before being randomised in a double blind study to receive either an acetylcholinesterase inhibitor (donepezil) or placebo for four months [9].
 

High impact information on CHRM1

  • tRNA precursor molecules that contain the CCA sequence found at the 3' termini of all mature tRNAs are cleaved in vitro more readily by M1 RNA, the catalytic subunit of E. coli RNAase P, than precursors that lack this sequence [10].
  • The human muscarinic subtype-1 receptor (HM1), which elicits PtdIns metabolism in neuronal cells through a G protein-coupled mechanism, also functionally activates this pathway when expressed in the T-cell line Jurkat-derived host, J-HM1-2.2 (ref.8) [11].
  • HM1 does not induce the tyrosine kinase pathway, suggesting that this pathway does not directly influence later T cell-activation responses [11].
  • In contrast, the HM1 and HM4 mAChRs strongly activate PI hydrolysis, but do not inhibit adenylyl cyclase, and in fact can substantially elevate cAMP levels [12].
  • Several HM1 alleles were generated and cloned by transposon-induced mutagenesis [13].
 

Chemical compound and disease context of CHRM1

  • Transient hypoxia induces sequestration of M1 and M2 muscarinic acetylcholine receptors [3].
  • It is concluded that IMR-32 and SK-N-MC neuroblastoma cells express muscarinic M1-type but not serotoninergic receptors coupled to phosphoinositide-specific phospholipase C. 8-OH-DPAT acts as a weak antagonist at these muscarinic receptors [14].
  • Antagonism by 8-hydroxy-2(di-n-propylamino)tetraline and other serotonin agonists of muscarinic M1-type receptors coupled to inositol phospholipid breakdown in human IMR-32 and SK-N-MC neuroblastoma cells [14].
  • Central muscarinic cholinergic activation by muscarine, the M1 receptor agonist McN-A-343, and the M2 receptor antagonist methoctramine inhibited serum TNF levels significantly during endotoxemia [15].
  • Nuclear estrogen binding was characterized in HM-1, a malignant hamster melanoma cell line transplanted into male and female athymic mice following acute, subchronic, and chronic injection of estradiol [16].
 

Biological context of CHRM1

  • Of these, 8 represent synonymous SNPs, indicating that CHRM1 is highly conserved in humans [17].
  • The consensus sequence of CHRM1 obtained in our study differs from the deposited reference sequence (AC NM_000738) in 2 adjacent nucleotides, leading to a V173M change, suggesting a sequencing error in the reference sequence [17].
  • Signaling via M1- and M3- but not M2- or M4-AchRs promote accumulation and transcriptional activation of HIF-1alpha [18].
  • Functional assays, using both M1 mAChR-mediated phosphoinositide hydrolysis and activation of neuronal nitric oxide synthase, confirmed that this persistent binding resulted in elevated basal levels of system activity [6].
  • The data suggest that increased phosphorylation of M1 and M2 mAChRs underlies the mechanism responsible for sequestration of these receptors following transient hypoxia [3].
 

Anatomical context of CHRM1

  • Expression of the M1, M2, and M3 muscarinic receptor subtypes was also confirmed in paraffin-embedded human small intestine sections by double immunofluorescent staining [19].
  • We investigated the molecular nature of the interaction between the functionally selective M1 muscarinic acetylcholine receptor (mAChR) agonist xanomeline and the human M1 mAChR expressed in Chinese hamster ovary (CHO) cells [6].
  • In patients with asthma, CHRM1 may be involved in airway constriction, airway epithelial cell proliferation, and airway inflammation [20].
  • These data suggest that acetylcholine acting on M1 and M2 receptors may contribute to selective excitability enhancement or depression in individual, rostrally projecting sensory neurons [21].
  • Furthermore, eEF1A1 or eEF1A2 had no effect on the recovery of the M1 subtype in PC12 cells [22].
 

Associations of CHRM1 with chemical compounds

  • McN-A-343 (M1 muscarinic agonist) dose dependently stimulated GLP-1 secretion (to 252 +/- 50% of control at 1000 microM; P < 0.01), whereas oxotremorine (M3 agonist) had no effect [19].
  • Pirenzepine (M1 antagonist; 10-1000 microM) and gallamine (M2 antagonist; 10-1000 microM) completely inhibited bethanechol-induced GLP-1 secretion, whereas 4-diphenylacetoxy-N-methylpiperidine (M3 antagonist) had no effect on bethanechol-stimulated GLP-1 secretion [19].
  • Sequence of the gene encoding the human M1 muscarinic acetylcholine receptor [23].
  • In contrast to the non-subtype-selective agonist carbachol, xanomeline demonstrated M1 mAChR binding that was resistant to extensive washout, resulting in a significant reduction in apparent N-[3H]methylscopolamine saturation binding affinity in intact cells [6].
  • Taken together, our findings indicate for the first time a novel mode of interaction between an mAChR agonist and the M1 mAChR, which may involve unusually avid binding of xanomeline to the receptor [6].
 

Regulatory relationships of CHRM1

  • Our previous studies showed the involvement of M1 muscarinic receptors expressed by the L cells in the regulation of postprandial GLP-1 secretion in rats [19].
 

Other interactions of CHRM1

  • All three patients with neuroleptic maliganant syndrome had high activities of autoantibodies to CHRM1, OPRM1, and/or HTR1A [1].
  • Hypoxia induced phosphorylation and sequestration of the M1 mAChR was, however, blocked by over-expression of a catalytically inactive casein kinase 1 alpha (CK1alpha K46R) [3].
  • They suggest a compact architecture for the muscarinic M1 receptor amino-terminal domain which may fold in a manner similar to that of rhodopsin [24].
  • Mutational analysis of third cytoplasmic loop domains in G-protein coupling of the HM1 muscarinic receptor [25].
  • A pharmacological profile of the methylenedioxy-substituted amphetamine derivatives indicates that MDMA and MDA exhibited highest affinity for serotonin uptake sites, 5-HT2 serotonin, alpha 2-adrenergic and M-1 muscarinic receptors [26].
 

Analytical, diagnostic and therapeutic context of CHRM1

  • M1, M2, and M3 muscarinic receptors were shown to be expressed in NCI-H716 cells by Western blot, immunohystochemistry, and RT-PCR [19].
  • As evidence for a physiological role of this modulatory mechanism, activation of the muscarinic receptor M1, a Galphaq-coupled receptor, promotes an increase in GRK2/Galphaq co-immunoprecipitation that parallels the enhanced GRK2 phosphorylation on tyrosine residues [27].
  • The diagnostic value of the PCR assay was evaluated in comparison to three other conventional H. meleagridis specific PCR tests (HIS5, HM1 and HM2) [28].
  • Immunoblotting analyses revealed that the polyclonal antibody and four (HM1, HM2, HM3 and HM4) of five monoclonal antibodies reacted with myosin heavy chain [29].
  • Experimental lesions using the retrogradely transported toxin, volkensin, have been used in conjunction with autoradiography to investigate the cellular localization of 5-HT1A, muscarinic M1 and nicotinic receptors [30].

References

  1. Autoantibodies against four kinds of neurotransmitter receptors in psychiatric disorders. Tanaka, S., Matsunaga, H., Kimura, M., Tatsumi, K., Hidaka, Y., Takano, T., Uema, T., Takeda, M., Amino, N. J. Neuroimmunol. (2003) [Pubmed]
  2. Autoantibodies against muscarinic cholinergic receptor in chronic fatigue syndrome. Tanaka, S., Kuratsune, H., Hidaka, Y., Hakariya, Y., Tatsumi, K.I., Takano, T., Kanakura, Y., Amino, N. Int. J. Mol. Med. (2003) [Pubmed]
  3. Transient hypoxia induces sequestration of M1 and M2 muscarinic acetylcholine receptors. Mou, L., Gates, A., Mosser, V.A., Tobin, A., Jackson, D.A. J. Neurochem. (2006) [Pubmed]
  4. Functional screening of drug target genes: m1 muscarinic acetylcholine receptor phenotypes in degenerative dementias. Weiner, D.M., Goodman, M.W., Colpitts, T.M., Feddock, M.A., Duggento, K.L., Nash, N.R., Levey, A.I., Brann, M.R. American journal of pharmacogenomics : genomics-related research in drug development and clinical practice. (2004) [Pubmed]
  5. The psychopharmacology of ziprasidone: receptor-binding properties and real-world psychiatric practice. Stahl, S.M., Shayegan, D.K. The Journal of clinical psychiatry. (2003) [Pubmed]
  6. On the unique binding and activating properties of xanomeline at the M1 muscarinic acetylcholine receptor. Christopoulos, A., Pierce, T.L., Sorman, J.L., El-Fakahany, E.E. Mol. Pharmacol. (1998) [Pubmed]
  7. Dose dependent inhibition of REM sleep in normal volunteers by biperiden, a muscarinic antagonist. Gillin, J.C., Sutton, L., Ruiz, C., Golshan, S., Hirsch, S., Warmann, C., Shiromani, P. Biol. Psychiatry (1991) [Pubmed]
  8. Alterations of muscarinic acetylcholine receptors in atypical Pick's disease without Pick bodies. Odawara, T., Shiozaki, K., Iseki, E., Hino, H., Kosaka, K. J. Neurol. Neurosurg. Psychiatr. (2003) [Pubmed]
  9. A randomised placebo controlled study to assess the effects of cholinergic treatment on muscarinic receptors in Alzheimer's disease. Kemp, P.M., Holmes, C., Hoffmann, S., Wilkinson, S., Zivanovic, M., Thom, J., Bolt, L., Fleming, J., Wilkinson, D.G. J. Neurol. Neurosurg. Psychiatr. (2003) [Pubmed]
  10. Cleavage of tRNA precursors by the RNA subunit of E. coli ribonuclease P (M1 RNA) is influenced by 3'-proximal CCA in the substrates. Guerrier-Takada, C., McClain, W.H., Altman, S. Cell (1984) [Pubmed]
  11. Stimulation of the phosphatidylinositol pathway can induce T-cell activation. Desai, D.M., Newton, M.E., Kadlecek, T., Weiss, A. Nature (1990) [Pubmed]
  12. Differential regulation of PI hydrolysis and adenylyl cyclase by muscarinic receptor subtypes. Peralta, E.G., Ashkenazi, A., Winslow, J.W., Ramachandran, J., Capon, D.J. Nature (1988) [Pubmed]
  13. Reductase activity encoded by the HM1 disease resistance gene in maize. Johal, G.S., Briggs, S.P. Science (1992) [Pubmed]
  14. Antagonism by 8-hydroxy-2(di-n-propylamino)tetraline and other serotonin agonists of muscarinic M1-type receptors coupled to inositol phospholipid breakdown in human IMR-32 and SK-N-MC neuroblastoma cells. Fowler, C.J., Ahlgren, P.C., O'Neill, C. Life Sci. (1991) [Pubmed]
  15. Central muscarinic cholinergic regulation of the systemic inflammatory response during endotoxemia. Pavlov, V.A., Ochani, M., Gallowitsch-Puerta, M., Ochani, K., Huston, J.M., Czura, C.J., Al-Abed, Y., Tracey, K.J. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  16. Effects of estradiol on estrogen receptor, progesterone receptor, and tyrosinase in hamster melanoma transplanted into athymic mice. Hitselberger, M.H., Schleicher, R.L., Beattie, C.W. Cancer Res. (1988) [Pubmed]
  17. Single nucleotide polymorphisms of the human M1 muscarinic acetylcholine receptor gene. Lucas, J.L., DeYoung, J.A., Sadee, W. AAPS PharmSci (2001) [Pubmed]
  18. Induction of hypoxia-inducible factor 1 activity by muscarinic acetylcholine receptor signaling. Hirota, K., Fukuda, R., Takabuchi, S., Kizaka-Kondoh, S., Adachi, T., Fukuda, K., Semenza, G.L. J. Biol. Chem. (2004) [Pubmed]
  19. Muscarinic receptors control glucagon-like peptide 1 secretion by human endocrine L cells. Anini, Y., Brubaker, P.L. Endocrinology (2003) [Pubmed]
  20. Polymorphisms in the muscarinic receptor 1 gene confer susceptibility to asthma in Japanese subjects. Maeda, Y., Hizawa, N., Jinushi, E., Honda, A., Takahashi, D., Fukui, Y., Konno, S., Shimizu, T., Shimizu, H., Yamaguchi, E., Nishimura, M. Am. J. Respir. Crit. Care Med. (2006) [Pubmed]
  21. Disparate cholinergic currents in rat principal trigeminal sensory nucleus neurons mediated by M1 and M2 receptors: a possible mechanism for selective gating of afferent sensory neurotransmission. Kohlmeier, K.A., Soja, P.J., Kristensen, M.P. Eur. J. Neurosci. (2006) [Pubmed]
  22. Elongation factor 1A family regulates the recycling of the M4 muscarinic acetylcholine receptor. McClatchy, D.B., Fang, G., Levey, A.I. Neurochem. Res. (2006) [Pubmed]
  23. Sequence of the gene encoding the human M1 muscarinic acetylcholine receptor. Allard, W.J., Sigal, I.S., Dixon, R.A. Nucleic Acids Res. (1987) [Pubmed]
  24. Fluorescence resonance energy transfer to probe human M1 muscarinic receptor structure and drug binding properties. Ilien, B., Franchet, C., Bernard, P., Morisset, S., Weill, C.O., Bourguignon, J.J., Hibert, M., Galzi, J.L. J. Neurochem. (2003) [Pubmed]
  25. Mutational analysis of third cytoplasmic loop domains in G-protein coupling of the HM1 muscarinic receptor. Arden, J.R., Nagata, O., Shockley, M.S., Philip, M., Lameh, J., Sadée, W. Biochem. Biophys. Res. Commun. (1992) [Pubmed]
  26. Pharmacologic profile of amphetamine derivatives at various brain recognition sites: selective effects on serotonergic systems. Battaglia, G., De Souza, E.B. NIDA Res. Monogr. (1989) [Pubmed]
  27. Tyrosine phosphorylation of G-protein-coupled-receptor kinase 2 (GRK2) by c-Src modulates its interaction with Galphaq. Mariggi??, S., Garc??a-Hoz, C., Sarnago, S., De Blasi, A., Mayor, F., Ribas, C. Cell. Signal. (2006) [Pubmed]
  28. Specific detection of Histomonas meleagridis in turkeys by a PCR assay with an internal amplification control. Bleyen, N., De Gussem, K., De Gussem, J., Goddeeris, B.M. Vet. Parasitol. (2007) [Pubmed]
  29. Monoclonal antibodies to rabbit hepatocyte myosin that cross-react with human liver myosin. Ueno, T., Watanabe, S., Hirose, M., Nozawa, R., Yasuura, S., Egawa, H., Sato, N., Kominami, E. J. Gastroenterol. Hepatol. (1996) [Pubmed]
  30. Acetylcholine receptor targets on cortical pyramidal neurones as targets for Alzheimer's therapy. Chessell, J.P. Neurodegeneration : a journal for neurodegenerative disorders, neuroprotection, and neuroregeneration. (1996) [Pubmed]
 
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