Muscarinic acetylcholine receptor M4

Cholinergic receptor, muscarinic 4

Identifiers

CHRM4 ; HM4; M4R

External IDs

OMIM: 118495 MGI: 88399 HomoloGene: 20192 IUPHAR: 16 ChEMBL: 1821 GeneCards: CHRM4 Gene

Gene ontology
Molecular function	• guanyl-nucleotide exchange factor activity • G-protein coupled acetylcholine receptor activity
Cellular component	• cytoplasm • plasma membrane • integral component of plasma membrane • postsynaptic density • cell junction • asymmetric synapse • sarcolemma • neuronal cell body • axon terminus • synapse • postsynaptic membrane
Biological process	• signal transduction • cell surface receptor signaling pathway • 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 • response to organic substance • positive regulation of adenylate cyclase activity involved in G-protein coupled receptor signaling pathway • regulation of locomotion • positive regulation of GTPase activity
Sources: Amigo / QuickGO

Orthologs

Species

Human

Mouse

RefSeq (mRNA)

RefSeq (protein)

Location (UCSC)

Chr 11:
46.39 – 46.39 Mb

Chr 2:
91.93 – 91.93 Mb

PubMed search

The muscarinic acetylcholine receptor M₄, also known as the cholinergic receptor, muscarinic 4 (CHRM4), is a protein that, in humans, is encoded by the CHRM4 gene.^[1]^[2]

Function

M₄ muscarinic receptors are coupled to G_i/o heterotrimeric proteins.^[3]

It function as inhibitory autoreceptors for acetylcholine. Activation of M₄ receptors inhibits acetylcholine release in the striatum. The M₂ subtype of acetylcholine receptor functions similarly as an inhibitory autoreceptor to acetylcholine release, albeit functioning actively primarily in the hippocampus and cerebral cortex.

Muscarinic acetylcholine receptors possess a regulatory effect on dopaminergic neurotransmission. Activation of M₄ receptors in the striatum inhibit D₁-induced locomotor stimulation in mice. M₄ receptor-deficient mice exhibit increased locomotor simulation in response to D₁ agonists, amphetamine and cocaine.^[4]^[5]^[6] Neurotransmission in the striatum influences extrapyramidal motor control, thus alterations in M₄ activity may contribute to conditions such as Parkinson's Disease.^[7]^[8]^[9]

Ligands

Orthosteric agonists

VU-0152100

Positive allosteric modulators

LY-2033298 ^[10]
VU-0152100 (ML-108) ^[11]^[12]^[13]^[14]^[15]^[16]
VU-0152099 ^[11]

Antagonists

AFDX-384 (mixed M2/M4 antagonist, N-[2-[2-[(Dipropylamino)methyl]-1-piperidinyl]ethyl]-5,6-dihydro-6-oxo-11H-pyrido[2,3-b][1,4]benzodiazepine-11-carboxamide, CAS# 118290-27-0)
Dicycloverine^[17]
Himbacine
Mamba toxin 3^[18]
PD-102,807 (3,6a,11,14-Tetrahydro-9-methoxy-2-methyl-(12H)-isoquino[1,2-b]pyrrolo[3,2-f][1,3]benzoxazine-1-carboxylic acid ethyl ester, CAS# 23062-91-1)
PD-0298029
Tropicamide - moderate selectivity over other muscarinic subtypes (2-5x approx)^[19]

References

↑ "Entrez Gene: CHRM4 cholinergic receptor, muscarinic 4".
↑ Grewal RP, Martinez M, Hoehe M, Bonner TI, Gershon ES, Detera-Wadleigh S (May 1992). "Genetic linkage mapping of the m4 human muscarinic receptor (CHRM4)". Genomics 13 (1): 239–40. doi:10.1016/0888-7543(92)90236-L. PMID 1577490.
↑ Qin K, Dong C, Wu G, Lambert NA (2011). "Inactive-state preassembly of G(q)-coupled receptors and G(q) heterotrimers". Nat. Chem. Biol. 7 (10): 740–7. doi:10.1038/nchembio.642. PMC 3177959. PMID 21873996.
↑ Gomeza J, Zhang L, Kostenis E, Felder C, Bymaster F, Brodkin J, Shannon H, Xia B, Deng C, Wess J (August 1999). "Enhancement of D1 dopamine receptor-mediated locomotor stimulation in M(4) muscarinic acetylcholine receptor knockout mice". Proceedings of the National Academy of Sciences of the United States of America 96 (18): 10483–8. doi:10.1073/pnas.96.18.10483. PMC 17915. PMID 10468635.
↑ Jeon J, Dencker D, Wörtwein G, Woldbye DP, Cui Y, Davis AA, Levey AI, Schütz G, Sager TN, Mørk A, Li C, Deng CX, Fink-Jensen A, Wess J (February 2010). "A subpopulation of neuronal M4 muscarinic acetylcholine receptors plays a critical role in modulating dopamine-dependent behaviors". J. Neurosci. 30 (6): 2396–405. doi:10.1523/JNEUROSCI.3843-09.2010. PMC 2824442. PMID 20147565.
↑ Schmidt LS, Thomsen M, Weikop P, Dencker D, Wess J, Woldbye DP, Wortwein G, Fink-Jensen A (2011). "Increased cocaine self-administration in M4 muscarinic acetylcholine receptor knockout mice". Psychopharmacology 216 (3): 367–378. doi:10.1007/s00213-011-2225-4. PMID 21373792.
↑ Langmead CJ, Watson J, Reavill C (February 2008). "Muscarinic acetylcholine receptors as CNS drug targets". Pharmacology & Therapeutics 117 (2): 232–43. doi:10.1016/j.pharmthera.2007.09.009. PMID 18082893.
↑ Stein IS, Hell JW (June 2010). "CaMKII hunkers down on the muscarinic M4 receptor to help curb cocaine-induced hyperlocomotion". The EMBO Journal 29 (12): 1943–5. doi:10.1038/emboj.2010.105. PMC 2892364. PMID 20551968.
↑ Guo ML, Mao LM, Wang JQ (December 2010). "Modulation of M4 muscarinic acetylcholine receptors by interacting proteins". Neuroscience Bulletin 26 (6): 469–73. doi:10.1007/s12264-010-0933-0. PMC 3139403. PMID 21113197.
↑ Chan WY, McKinzie DL, Bose S, Mitchell SN, Witkin JM, Thompson RC, Christopoulos A, Lazareno S, Birdsall NJ, Bymaster FP, Felder CC (2008). "Allosteric modulation of the muscarinic M4 receptor as an approach to treating schizophrenia". PNAS 105 (31): 10978–83. doi:10.1073/pnas.0800567105. PMC 2495016. PMID 18678919.
1 2 Brady AE, Jones CK, Bridges TM, Kennedy JP, Thompson AD, Heiman JU, Breininger ML, Gentry PR, Yin H, Jadhav SB, Shirey JK, Conn PJ, Lindsley CW (2008). "Centrally active allosteric potentiators of the M4 muscarinic acetylcholine receptor reverse amphetamine-induced hyperlocomotor activity in rats". J. Pharmacol. Exp. Ther. 327 (3): 941–53. doi:10.1124/jpet.108.140350. PMC 2745822. PMID 18772318.
↑ Dencker D, Weikop P, Sørensen G, et al. (2012). "An allosteric enhancer of M₄ muscarinic acetylcholine receptor function inhibits behavioral and neurochemical effects of cocaine". Psychopharmacology (Berl.) 224 (2): 277–87. doi:10.1007/s00213-012-2751-8. PMC 3914671. PMID 22648127.
↑ Byun NE, Grannan M, Bubser M, et al. (2014). "Antipsychotic drug-like effects of the selective M4 muscarinic acetylcholine receptor positive allosteric modulator VU0152100". Neuropsychopharmacology 39 (7): 1578–93. doi:10.1038/npp.2014.2. PMID 24442096.
↑ Galloway CR, Lebois EP, Shagarabi SL, Hernandez NA, Manns JR (2014). "Effects of selective activation of M1 and M4 muscarinic receptors on object recognition memory performance in rats". Pharmacology 93 (1-2): 57–64. doi:10.1159/000357682. PMID 24480931.
↑ Pancani T, Bolarinwa C, Smith Y, Lindsley CW, Conn PJ, Xiang Z (2014). "M4 mAChR-mediated modulation of glutamatergic transmission at corticostriatal synapses". ACS Chem Neurosci 5 (4): 318–24. doi:10.1021/cn500003z. PMID 24528004.
↑ Huynh T, Valant C, Crosby IT, Sexton PM, Christopoulos A, Capuano B (2013). "Probing structural requirements of positive allosteric modulators of the M4 muscarinic receptor". J. Med. Chem. 56 (20): 8196–200. doi:10.1021/jm401032k. PMID 24074052.
↑ Teaktong T, Piggott MA, Mckeith IG, Perry RH, Ballard CG, Perry EK (June 2005). "Muscarinic M2 and M4 receptors in anterior cingulate cortex: relation to neuropsychiatric symptoms in dementia with Lewy bodies". Behavioural Brain Research 161 (2): 299–305. doi:10.1016/j.bbr.2005.02.019. PMID 15922057.
↑ http://www.uniprot.org/uniprot/P81031
↑ Lazareno S, Buckley NJ, Roberts FF (December 1990). "Characterization of muscarinic M4 binding sites in rabbit lung, chicken heart, and NG108-15 cells". Molecular Pharmacology 38 (6): 805–15. PMID 2250662.

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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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