Muscarinic acetylcholine receptor M4

From Wikipedia, the free encyclopedia
Jump to: navigation, search
Cholinergic receptor, muscarinic 4
Identifiers
Symbols CHRM4 ; HM4; M4R
External IDs OMIM118495 MGI88399 HomoloGene20192 IUPHAR: M4 ChEMBL: 1821 GeneCards: CHRM4 Gene
Orthologs
Species Human Mouse
Entrez 1132 12672
Ensembl ENSG00000180720 ENSMUSG00000040495
UniProt P08173 P32211
RefSeq (mRNA) NM_000741 NM_007699
RefSeq (protein) NP_000732 NP_031725
Location (UCSC) Chr 11:
46.41 – 46.41 Mb
Chr 2:
91.92 – 91.93 Mb
PubMed search [1] [2]

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[edit]

M4 muscarinic receptors are coupled to Gi/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[edit]

Orthosteric agonists[edit]

Allosteric Agonists[edit]

Antagonists[edit]

  • 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[12]
  • Himbacine
  • Mamba toxin 3[13]
  • 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)[14]

See also[edit]

References[edit]

  1. ^ "Entrez Gene: CHRM4 cholinergic receptor, muscarinic 4". 
  2. ^ 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. 
  3. ^ 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. 
  4. ^ 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. 
  5. ^ 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. 
  6. ^ 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. 
  7. ^ 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. 
  8. ^ 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. 
  9. ^ 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. 
  10. ^ 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. 
  11. ^ 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. 
  12. ^ 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. 
  13. ^ http://www.uniprot.org/uniprot/P81031
  14. ^ 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. 

Further reading[edit]

This article incorporates text from the United States National Library of Medicine, which is in the public domain.