Muscarinic acetylcholine receptor M5

Cholinergic receptor, muscarinic 5

Identifiers

CHRM5 ; HM5

External IDs

OMIM: 118496 MGI: 109248 HomoloGene: 22697 IUPHAR: 17 ChEMBL: 2035 GeneCards: CHRM5 Gene

Gene ontology
Molecular function	• phosphatidylinositol phospholipase C activity • G-protein coupled acetylcholine receptor activity
Cellular component	• plasma membrane • integral component of plasma membrane • cell junction • synapse • postsynaptic membrane
Biological process	• gastric acid secretion • adenylate cyclase-inhibiting G-protein coupled acetylcholine receptor signaling pathway • phospholipase C-activating G-protein coupled acetylcholine receptor signaling pathway • G-protein coupled acetylcholine receptor signaling pathway • synaptic transmission, cholinergic • sensory perception of chemical stimulus • cell proliferation • positive regulation of adenylate cyclase activity involved in G-protein coupled receptor signaling pathway • dopamine transport • transmission of nerve impulse • regulation of phosphatidylinositol dephosphorylation
Sources: Amigo / QuickGO

RNA expression pattern

More reference expression data

Orthologs

Species

Human

Mouse

RefSeq (mRNA)

RefSeq (protein)

Location (UCSC)

Chr 15:
33.97 – 34.07 Mb

Chr 2:
112.48 – 112.48 Mb

PubMed search

The human muscarinic acetylcholine receptor M₅, encoded by the CHRM5 gene, is a member of the G protein-coupled receptor superfamily of integral membrane proteins. It is coupled to G_q protein.^[1] Binding of the endogenous ligand acetylcholine to the M₅ receptor triggers a number of cellular responses such as adenylate cyclase inhibition, phosphoinositide degradation, and potassium channel modulation. Muscarinic receptors mediate many of the effects of acetylcholine in the central and peripheral nervous system. The clinical implications of this receptor have not been fully explored; however, stimulation of this receptor is known to effectively decrease cyclic AMP levels and downregulate the activity of protein kinase A (PKA).

Ligands

No highly selective agonists or antagonists for the M₅ receptor have been discovered as of 2009, but several non-selective muscarinic agonists and antagonists have significant affinity for M₅.

The lack of selective M5 receptor ligands is one of the main reasons that the medical community has such a limited understanding of the M5 receptors effects as the possibility that any and/or all effects of non-selective ligands may be due to interactions with other receptors can not be ruled out. Some data may be obtained by observing which effects are common among semi-selective ligands (ex. a ligand of M1 and M5, a ligand of M2 and M5, and a ligand of M3 and M5), but until both a selective agonist and a selective antagonist of the M5 receptor are developed this data must be considered merely theoretical.

Agonists

Milameline ((E)-1,2,5,6-Tetrahydro-1-methyl-3-pyridinecarboxaldehyde-O-methyloxime, CAS# 139886-32-1)
Sabcomeline

Positive allosteric modulators

ML-380^[2]
ML-326^[3]
VU-0238429: EC₅₀ = 1.16 μM; >30-fold selectivity versus M1 and M3, inactive at M2 and M4.^[4]

Negative allosteric modulators

ML375^[5]

Antagonists

VU-0488130 (ML381)^[6]
Xanomeline^[7]

References

↑ Kou Qin, Chunmin Dong, Guangyu Wu & Nevin A Lambert (August 2011). "Inactive-state preassembly of Gq-coupled receptors and Gq heterotrimers". Nature Chemical Biology 7 (11): 740–747. doi:10.1038/nchembio.642. PMC 3177959. PMID 21873996.
↑ Gentry PR, Kokubo M, Bridges TM, et al. (2014). "Development of a Highly Potent, Novel M5 Positive Allosteric Modulator (PAM) Demonstrating CNS Exposure: 1-((1H-Indazol-5-yl)sulfoneyl)-N-ethyl-N-(2-(trifluoromethyl)benzyl)piperidine-4-carboxamide (ML380)". J. Med. Chem. 57: 7804–10. doi:10.1021/jm500995y. PMID 25147929.
↑ Gentry PR, Bridges TM, Lamsal A, et al. (2013). "Discovery of ML326: The first sub-micromolar, selective M5 PAM". Bioorg. Med. Chem. Lett. 23 (10): 2996–3000. doi:10.1016/j.bmcl.2013.03.032. PMID 23562060.
↑ Bridges TM, Marlo JE, Niswender CM, et al. (June 2009). "Discovery of the first highly M5-preferring muscarinic acetylcholine receptor ligand, an M5 positive allosteric modulator derived from a series of 5-trifluoromethoxy N-benzyl isatins". J. Med. Chem. 52 (11): 3445–8. doi:10.1021/jm900286j. PMID 19438238.
↑ Gentry PR, Kokubo M, Bridges TM, et al. (2013). "Discovery of the first M5-selective and CNS penetrant negative allosteric modulator (NAM) of a muscarinic acetylcholine receptor: (S)-9b-(4-chlorophenyl)-1-(3,4-difluorobenzoyl)-2,3-dihydro-1H-imidazo[2,1-a]isoindol-5(9bH)-one (ML375)". J. Med. Chem. 56 (22): 9351–5. doi:10.1021/jm4013246. PMID 24164599.
↑ Gentry PR, Kokubo M, Bridges TM, et al. (2014). "Discovery, Synthesis and Characterization of a Highly Muscarinic Acetylcholine Receptor (mAChR)-Selective M5 -Orthosteric Antagonist, VU0488130 (ML381): A Novel Molecular Probe". ChemMedChem 9 (8): 1677–82. doi:10.1002/cmdc.201402051. PMID 24692176.
↑ Grant MK, El-Fakahany EE (October 2005). "Persistent binding and functional antagonism by xanomeline at the muscarinic M₅ receptor". J. Pharmacol. Exp. Ther. 315 (1): 313–9. doi:10.1124/jpet.105.090134. PMID 16002459.

Brann MR, Ellis J, Jørgensen H, et al. (1994). "Muscarinic acetylcholine receptor subtypes: localization and structure/function.". Prog. Brain Res. 98: 121–7. doi:10.1016/S0079-6123(08)62388-2. PMID 8248499.
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Liao CF, Themmen AP, Joho R, et al. (1989). "Molecular cloning and expression of a fifth muscarinic acetylcholine receptor.". J. Biol. Chem. 264 (13): 7328–37. PMID 2540186.
Bonner TI, Young AC, Brann MR, Buckley NJ (1990). "Cloning and expression of the human and rat m5 muscarinic acetylcholine receptor genes.". Neuron 1 (5): 403–10. doi:10.1016/0896-6273(88)90190-0. PMID 3272174.
Crespo P, Xu N, Daniotti JL, et al. (1994). "Signaling through transforming G protein-coupled receptors in NIH 3T3 cells involves c-Raf activation. Evidence for a protein kinase C-independent pathway.". J. Biol. Chem. 269 (33): 21103–9. PMID 8063729.
Haga K, Kameyama K, Haga T, et al. (1996). "Phosphorylation of human m1 muscarinic acetylcholine receptors by G protein-coupled receptor kinase 2 and protein kinase C.". J. Biol. Chem. 271 (5): 2776–82. doi:10.1074/jbc.271.5.2776. PMID 8576254.
Kohn EC, Alessandro R, Probst J, et al. (1996). "Identification and molecular characterization of a m5 muscarinic receptor in A2058 human melanoma cells. Coupling to inhibition of adenylyl cyclase and stimulation of phospholipase A2.". J. Biol. Chem. 271 (29): 17476–84. doi:10.1074/jbc.271.29.17476. PMID 8663391.
Burstein ES, Spalding TA, Brann MR (1998). "The second intracellular loop of the m5 muscarinic receptor is the switch which enables G-protein coupling.". J. Biol. Chem. 273 (38): 24322–7. doi:10.1074/jbc.273.38.24322. PMID 9733718.
Sato KZ, Fujii T, Watanabe Y, et al. (1999). "Diversity of mRNA expression for muscarinic acetylcholine receptor subtypes and neuronal nicotinic acetylcholine receptor subunits in human mononuclear leukocytes and leukemic cell lines.". Neurosci. Lett. 266 (1): 17–20. doi:10.1016/S0304-3940(99)00259-1. PMID 10336173.
Wang H, Han H, Zhang L, et al. (2001). "Expression of multiple subtypes of muscarinic receptors and cellular distribution in the human heart.". Mol. Pharmacol. 59 (5): 1029–36. PMID 11306684.
Buchli R, Ndoye A, Arredondo J, et al. (2002). "Identification and characterization of muscarinic acetylcholine receptor subtypes expressed in human skin melanocytes.". Mol. Cell. Biochem. 228 (1–2): 57–72. doi:10.1023/A:1013368509855. PMID 11855742.
Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
Fujii T, Watanabe Y, Inoue T, Kawashima K (2003). "Upregulation of mRNA encoding the M5 muscarinic acetylcholine receptor in human T- and B-lymphocytes during immunological responses". Neurochem. Res. 28 (3–4): 423–9. doi:10.1023/A:1022840416292. PMID 12675126.
Ota T, Suzuki Y, Nishikawa T, et al. (2004). "Complete sequencing and characterization of 21,243 full-length human cDNAs". Nat. Genet. 36 (1): 40–5. doi:10.1038/ng1285. PMID 14702039.
De Luca V, Wang H, Squassina A, et al. (2004). "Linkage of M5 muscarinic and alpha7-nicotinic receptor genes on 15q13 to schizophrenia". Neuropsychobiology 50 (2): 124–7. doi:10.1159/000079102. PMID 15292665.
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This article incorporates text from the United States National Library of Medicine, which is in the public domain.

Cell surface receptor: G protein-coupled receptors

Class A: Rhodopsin like

Neurotransmitter

Adrenergic	α1 (A B D) α2 (A B C) β1 β2 β3

Purinergic	Adenosine (A1 A2A A2B A3) P2Y (1 2 4 5 6 8 9 10 11 12 13 14)

Serotonin	(all but 5-HT3) 5-HT1 (A B D E F) 5-HT2 (A B C) 5-HT (4 5A 6 7)

Other	Acetylcholine (M1 M2 M3 M4 M5) Dopamine (D1 D2 D3 D4 D5) Histamine (H1 H2 H3 H4) Melatonin (1A 1B 1C) TAAR (1 2 3 5 6 8 9)

Metabolites and
signaling molecules

Eicosanoid	CysLT (1 2) LTB4 (1 2) FPRL1 OXE Prostaglandin (DP (1 2), EP (1 2 3 4), FP) Prostacyclin Thromboxane

Other	Bile acid Cannabinoid (CB1 CB2, GPR (18 55 119)) EBI2 Estrogen Free fatty acid (1 2 3 4) Lactate Lysophosphatidic acid (1 2 3 4 5 6) Lysophospholipid (1 2 3 4 5 6 7 8) Niacin (1 2) Oxoglutarate PAF Sphingosine-1-phosphate (1 2 3 4 5) Succinate

Peptide

Neuropeptide	B/W (1 2) FF (1 2) S Y (1 2 4 5) Neuromedin (B U (1 2)) Neurotensin (1 2)

Other	Anaphylatoxin (C3a C5a) Angiotensin (1 2) Apelin Bombesin (BRS3 GRPR NMBR) Bradykinin (B1 B2) Chemokine Cholecystokinin (A B) Endothelin (A B) Formyl peptide (1 2 3) FSH Galanin (1 2 3) GHB receptor Gonadotropin-releasing hormone (1 2) Ghrelin Kisspeptin Luteinizing hormone/choriogonadotropin MAS (1 1L D E F G X1 X2 X3 X4) Melanocortin (1 2 3 4 5) MCHR (1 2) Motilin Opioid (Delta Kappa Mu Nociceptin & Zeta, but not Sigma) Orexin (1 2) Oxytocin Prokineticin (1 2) Prolactin-releasing peptide Relaxin (1 2 3 4) Somatostatin (1 2 3 4 5) Tachykinin (1 2 3) Thyrotropin Thyrotropin-releasing hormone Urotensin-II Vasopressin (1A 1B 2)

Miscellaneous

Orphan	GPR (1 3 4 6 12 15 17 18 19 20 21 22 23 25 26 27 31 32 33 34 35 37 39 42 44 45 50 52 55 61 62 63 65 68 75 77 78 81 82 83 84 85 87 88 92 101 103 109A 109B 119 120 132 135 137B 139 141 142 146 148 149 150 151 152 153 160 161 162 171 173 174 176 177 182 183)

Other	Adrenomedullin Olfactory Opsin (3 4 5 1LW 1MW 1SW RGR RRH) Protease-activated (1 2 3 4) SREB (1 2 3)

Class B: Secretin like

Adhesion	ADGRG (1 2 3 4 5 6 7)

Orphan	GPR (56 64 97 98 110 111 112 113 114 115 116 123 124 125 126 128 133 143 144 155 157)

Other	Brain-specific angiogenesis inhibitor (1 2 3) Cadherin (1 2 3) Calcitonin CALCRL CD97 Corticotropin-releasing hormone (1 2) EMR (1 2 3) Glucagon (GR GIPR GLP1R GLP2R) Growth hormone releasing hormone PACAPR1 GPR Latrophilin (1 2 3 ELTD1) Methuselah-like proteins Parathyroid hormone (1 2) Secretin Vasoactive intestinal peptide (1 2)

Class C: Metabotropic glutamate / pheromone

Taste	TAS1R (1 2 3) TAS2R (1 3 4 5 7 8 9 10 13 14 16 19 20 30 31 38 39 40 41 42 43 45 46 50 60)

Other	Calcium-sensing receptor GABA B (1 2) Glutamate receptor (Metabotropic glutamate (1 2 3 4 5 6 7 8)) GPRC6A GPR (156 158 179) RAIG (1 2 3 4)

Class F: Frizzled / Smoothened

Frizzled	Frizzled (1 2 3 4 5 6 7 8 9 10)

Smoothened	Smoothened

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