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Chrm5  -  cholinergic receptor, muscarinic 5

Mus musculus

Synonyms: AChR-M5, M5R, Muscarinic acetylcholine receptor M5, m5, muscarinic acetylcholine receptor 5
 
 
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Psychiatry related information on Chrm5

  • The finding that M5 receptor activity modulates both morphine reward and withdrawal processes suggests that M5 receptors may represent a novel target for the treatment of opiate addiction [1].
 

High impact information on Chrm5

  • In the brain, the M5 receptor subtype is preferentially expressed by dopaminergic neurons of the substantia nigra and the ventral tegmental area [1].
  • This effect was specific for cerebral blood vessels, because acetylcholine-mediated dilation of extra-cerebral arteries remained fully intact in M5R(-/-) mice [2].
  • Strikingly, acetylcholine, a powerful dilator of most vascular beds, virtually lost the ability to dilate cerebral arteries and arterioles in M5R(-/-) mice [2].
  • Of the five signaling pathways associated with the m1, m3, and m5 receptors, only receptor-operated, and inositol trisphosphate-independent, calcium influx was found to correlate with inhibition of tumorigenicity [3].
  • In contrast, when cultures were supplemented with carbachol, a stable analog of acetylcholine, foci of transformation readily appeared in m1, m3, or m5 but not in m2 or m4 mAChRs transfectants [4].
 

Biological context of Chrm5

  • In M5R(-/-) mice, CA3 pyramidal cells displayed a significantly attenuated frequency of the spontaneous postsynaptic current and long-term potentiation was significantly impaired at the mossy fiber-CA3 synapse [5].
  • To define their structural requirements, we have subjected the N- and C-terminal regions of this loop (Ni3 and Ci3, respectively) of the m5 muscarinic receptor to random saturation mutagenesis [6].
  • Despite this, the M5 receptor still activated tyrosine kinases, induced STAT1 tyrosine phosphorylation, and stimulated cell proliferation [7].
  • Those mAChR subtypes efficiently coupled to PIP2 hydrolysis (m1, m3 and m5) induced agonist-dependent cell transformation whereas those inhibiting adenylyl cyclase (m2, m4) lack transforming activity [8].
  • The m5 muscarinic acetylcholine receptor was constitutively activated by a wide range of amino acid substitutions at a residue (serine 465) that is positioned at the junction of the sixth transmembrane domain and the extracellular loop [9].
 

Anatomical context of Chrm5

  • The respective pKi values for R-(+)- and S-(-)-hyoscyamine vs the five human muscarinic receptor subtypes expressed in Chinese hamster oocytes (CHO-K1) were as follows: 8.21 +/- 0.07/9.48 +/- 0.18 for m1; 7.89 +/- 0.06/9.45 +/- 0.31 for m2; 8.06 +/- 0.18/9.30 +/- 0.19 for m3; 8.35 +/- 0.11/9.55 +/- 0.13 for m4; 8.17 +/- 0.08/9.24 +/- 0.30 for m5 [10].
  • Male M5R(-/-) mice exhibited a significantly reduced cerebral blood flow (CBF) in the cerebral cortex, hippocampus, basal ganglia, and thalamus [5].
  • The relative functional contributions of all amino acids within Ni3 was evaluated by constructing libraries of m5 muscarinic receptors containing random mutations in Ni3 and screening them using high throughput assays based on ligand-dependent transformation of NIH 3T3 cells [11].
  • Previously, we reported that disruption of the M5 receptor gene in mice reduced dopamine release in the nucleus accumbens [12].
  • 3. In CHO cells, receptor-effector coupling efficiencies were m3 = m1 > m5 [13].
 

Associations of Chrm5 with chemical compounds

  • Strikingly, oxotremorine-mediated potentiation of stimulated striatal [3H]dopamine release was abolished in M4 receptor KO mice, significantly increased in M3 receptor-deficient mice, and significantly reduced (but not abolished) in M5 receptor KO mice [14].
  • When transfected and expressed in CHO-K1 Chinese hamster ovary cells, m1, m3, and m5 muscarinic acetylcholine receptor activation resulted in a morphology change [3].
  • The cloning and functional expression of five mammalian muscarinic acetylcholine receptor genes (m1-m5) has revealed that m1, m3, and m5 primarily couple to stimulation of phosphoinositide (PI) turnover, whereas m2 and m4 are strongly linked to inhibition of adenylate cyclase, albeit not exclusively [15].
  • Our results indicate that M5 receptor deletion diminished the reinforcing effects of low doses of cocaine and identified specific conditions under which this may be observed [16].
  • Although CHOm5 receptors were the least efficiently coupled, some partial agonists displayed higher intrinsic efficacies at m5 than m3 receptors suggesting that, in CHO cells, m5 and m3 receptors may activate different G proteins and/or effectors to stimulate inositol monophosphate (IP1) formation [13].
 

Analytical, diagnostic and therapeutic context of Chrm5

  • To circumvent these difficulties, we used gene targeting technology to generate M(5) receptor-deficient mice (M5R(-/-) mice) [2].
  • We show that male M5R(-/-) mice displayed constitutive constriction of cerebral arteries using magnetic resonance angiography in vivo [5].
  • We tested the hypothesis that the reinforcing effects of cocaine are decreased in M5 receptor-deficient mice using chronic intravenous cocaine self-administration in extensively backcrossed mice [16].
  • PCR products corresponding to subtypes m1, m3, and m5, but not to m2 and m4, were amplified [17].
  • Stimulation of the ml, m3 and m5 muscarinic receptors in the NIH 3T3 cell resulted in dose-dependent increases in the concentration of intracellular cAMP in comparison to control as determined by cAMP immunoassay [18].

References

  1. Deletion of the M5 muscarinic acetylcholine receptor attenuates morphine reinforcement and withdrawal but not morphine analgesia. Basile, A.S., Fedorova, I., Zapata, A., Liu, X., Shippenberg, T., Duttaroy, A., Yamada, M., Wess, J. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  2. Cholinergic dilation of cerebral blood vessels is abolished in M(5) muscarinic acetylcholine receptor knockout mice. Yamada, M., Lamping, K.G., Duttaroy, A., Zhang, W., Cui, Y., Bymaster, F.P., McKinzie, D.L., Felder, C.C., Deng, C.X., Faraci, F.M., Wess, J. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  3. Tumor-suppressor function of muscarinic acetylcholine receptors is associated with activation of receptor-operated calcium influx. Felder, C.C., MacArthur, L., Ma, A.L., Gusovsky, F., Kohn, E.C. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  4. Muscarinic acetylcholine receptor subtypes as agonist-dependent oncogenes. Gutkind, J.S., Novotny, E.A., Brann, M.R., Robbins, K.C. Proc. Natl. Acad. Sci. U.S.A. (1991) [Pubmed]
  5. Loss of M(5) muscarinic acetylcholine receptors leads to cerebrovascular and neuronal abnormalities and cognitive deficits in mice. Araya, R., Noguchi, T., Yuhki, M., Kitamura, N., Higuchi, M., Saido, T.C., Seki, K., Itohara, S., Kawano, M., Tanemura, K., Takashima, A., Yamada, K., Kondoh, Y., Kanno, I., Wess, J., Yamada, M. Neurobiol. Dis. (2006) [Pubmed]
  6. Amino acid side chains that define muscarinic receptor/G-protein coupling. Studies of the third intracellular loop. Burstein, E.S., Spalding, T.A., Brann, M.R. J. Biol. Chem. (1996) [Pubmed]
  7. Tyrosine kinase activation by the angiotensin II receptor in the absence of calcium signaling. Doan, T.N., Ali, M.S., Bernstein, K.E. J. Biol. Chem. (2001) [Pubmed]
  8. Transforming G protein-coupled receptors transduce potent mitogenic signals in NIH 3T3 cells independent on cAMP inhibition or conventional protein kinase C. Stephens, E.V., Kalinec, G., Brann, M.R., Gutkind, J.S. Oncogene (1993) [Pubmed]
  9. Constitutive activation of the m5 muscarinic receptor by a series of mutations at the extracellular end of transmembrane 6. Spalding, T.A., Burstein, E.S., Wells, J.W., Brann, M.R. Biochemistry (1997) [Pubmed]
  10. Stereoselective increase in cholinergic transmission by R-(+)-hyoscyamine. Ghelardini, C., Gualtieri, F., Novella Romanelli, M., Angeli, P., Pepeu, G., Grazia Giovannini, M., Casamenti, F., Malmberg-Aiello, P., Giotti, A., Bartolini, A. Neuropharmacology (1997) [Pubmed]
  11. Structure of a G-protein-coupling domain of a muscarinic receptor predicted by random saturation mutagenesis. Hill-Eubanks, D., Burstein, E.S., Spalding, T.A., Bräuner-Osborne, H., Brann, M.R. J. Biol. Chem. (1996) [Pubmed]
  12. Decreased amphetamine-induced locomotion and improved latent inhibition in mice mutant for the M5 muscarinic receptor gene found in the human 15q schizophrenia region. Wang, H., Ng, K., Hayes, D., Gao, X., Forster, G., Blaha, C., Yeomans, J. Neuropsychopharmacology (2004) [Pubmed]
  13. Human muscarinic receptors expressed in A9L and CHO cells: activation by full and partial agonists. Richards, M.H., van Giersbergen, P.L. Br. J. Pharmacol. (1995) [Pubmed]
  14. Multiple muscarinic acetylcholine receptor subtypes modulate striatal dopamine release, as studied with M1-M5 muscarinic receptor knock-out mice. Zhang, W., Yamada, M., Gomeza, J., Basile, A.S., Wess, J. J. Neurosci. (2002) [Pubmed]
  15. Delineation of muscarinic receptor domains conferring selectivity of coupling to guanine nucleotide-binding proteins and second messengers. Wess, J., Bonner, T.I., Dörje, F., Brann, M.R. Mol. Pharmacol. (1990) [Pubmed]
  16. Reduced cocaine self-administration in muscarinic M5 acetylcholine receptor-deficient mice. Thomsen, M., Woldbye, D.P., Wörtwein, G., Fink-Jensen, A., Wess, J., Caine, S.B. J. Neurosci. (2005) [Pubmed]
  17. Analysis of muscarinic receptor subtypes in the mouse cochlea by means of the polymerase chain reaction. Drescher, D.G., Upadhyay, S., Wilcox, E., Fex, J. J. Neurochem. (1992) [Pubmed]
  18. Modulation of low-threshold T-type calcium channels by the five muscarinic receptor subtypes in NIH 3T3 cells. Pemberton, K.E., Hill-Eubanks, L.J., Jones, S.V. Pflugers Arch. (2000) [Pubmed]
 
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