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Muscarinic acetylcholine receptor M4

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Muscarinic acetylcholine receptor M4

Cholinergic receptor, muscarinic 4
Symbols  ; HM4; M4R
External IDs IUPHAR: ChEMBL: GeneCards:
Species Human Mouse
RefSeq (mRNA)
RefSeq (protein)
Location (UCSC)
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]


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]


Orthosteric agonists


Positive allosteric modulators


  • 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]

See also


  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.  
  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.  
  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.  
  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.  
  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.  
  7. ^ Langmead CJ, Watson J, Reavill C (February 2008). "Muscarinic acetylcholine receptors as CNS drug targets". Pharmacology & Therapeutics 117 (2): 232–43.  
  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.  
  9. ^ Guo ML, Mao LM, Wang JQ (December 2010). "Modulation of M4 muscarinic acetylcholine receptors by interacting proteins". Neuroscience Bulletin 26 (6): 469–73.  
  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.  
  11. ^ a b 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.  
  12. ^ 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.  
  13. ^ 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.  
  14. ^ 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.  
  15. ^ 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.  
  16. ^ 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.  
  17. ^ 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.  
  18. ^
  19. ^ 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.  

Further reading

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