Muscarinic acetylcholine receptor M4 explained

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 Gi/o heterotrimeric proteins.[3]

They 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

Positive allosteric modulators

Antagonists

See also

Further reading

Notes and References

  1. Web site: Entrez Gene: CHRM4 cholinergic receptor, muscarinic 4.
  2. Grewal RP, Martinez M, Hoehe M, Bonner TI, Gershon ES, Detera-Wadleigh S . Genetic linkage mapping of the m4 human muscarinic receptor (CHRM4) . Genomics . 13 . 1 . 239–40 . May 1992 . 1577490 . 10.1016/0888-7543(92)90236-L .
  3. Qin K, Dong C, Wu G, Lambert NA . Inactive-state preassembly of G(q)-coupled receptors and G(q) heterotrimers . Nat. Chem. Biol. . 7 . 10 . 740–7 . 2011 . 21873996 . 3177959 . 10.1038/nchembio.642 .
  4. Gomeza J, Zhang L, Kostenis E, Felder C, Bymaster F, Brodkin J, Shannon H, Xia B, Deng C, Wess J . 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 . August 1999 . 10468635 . 17915 . 10.1073/pnas.96.18.10483 . 1999PNAS...9610483G . free .
  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 . A subpopulation of neuronal M4 muscarinic acetylcholine receptors plays a critical role in modulating dopamine-dependent behaviors . J. Neurosci. . 30 . 6 . 2396–405 . February 2010 . 20147565 . 2824442 . 10.1523/JNEUROSCI.3843-09.2010 .
  6. Schmidt LS, Thomsen M, Weikop P, Dencker D, Wess J, Woldbye DP, Wortwein G, Fink-Jensen A . Increased cocaine self-administration in M4 muscarinic acetylcholine receptor knockout mice . Psychopharmacology . 216 . 3 . 367–378 . 2011 . 21373792 . 3899540. 10.1007/s00213-011-2225-4 .
  7. Langmead CJ, Watson J, Reavill C . Muscarinic acetylcholine receptors as CNS drug targets . Pharmacology & Therapeutics . 117 . 2 . 232–43 . February 2008 . 18082893 . 10.1016/j.pharmthera.2007.09.009 .
  8. Stein IS, Hell JW . CaMKII hunkers down on the muscarinic M4 receptor to help curb cocaine-induced hyperlocomotion . The EMBO Journal . 29 . 12 . 1943–5 . June 2010 . 20551968 . 2892364 . 10.1038/emboj.2010.105 .
  9. Guo ML, Mao LM, Wang JQ . Modulation of M4 muscarinic acetylcholine receptors by interacting proteins . Neuroscience Bulletin . 26 . 6 . 469–73 . December 2010 . 21113197 . 3139403 . 10.1007/s12264-010-0933-0 .
  10. Chan WY, McKinzie DL, Bose S, Mitchell SN, Witkin JM, Thompson RC, Christopoulos A, Lazareno S, Birdsall NJ, Bymaster FP, Felder CC . Allosteric modulation of the muscarinic M4 receptor as an approach to treating schizophrenia . PNAS . 105 . 31 . 10978–83 . 2008 . 18678919 . 2495016 . 10.1073/pnas.0800567105 . 2008PNAS..10510978C . free .
  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 . 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 . 2008 . 18772318 . 2745822 . 10.1124/jpet.108.140350 .
  12. Dencker D, Weikop P, Sørensen G, etal . An allosteric enhancer of M4 muscarinic acetylcholine receptor function inhibits behavioral and neurochemical effects of cocaine . Psychopharmacology . 224 . 2 . 277–87 . 2012 . 22648127 . 3914671 . 10.1007/s00213-012-2751-8 .
  13. Byun NE, Grannan M, Bubser M, etal . Antipsychotic drug-like effects of the selective M4 muscarinic acetylcholine receptor positive allosteric modulator VU0152100 . Neuropsychopharmacology . 39 . 7 . 1578–93 . 2014 . 24442096 . 10.1038/npp.2014.2 . 4023154.
  14. Galloway CR, Lebois EP, Shagarabi SL, Hernandez NA, Manns JR . Effects of selective activation of M1 and M4 muscarinic receptors on object recognition memory performance in rats . Pharmacology . 93 . 1–2 . 57–64 . 2014 . 24480931 . 10.1159/000357682 . 10402346 .
  15. Pancani T, Bolarinwa C, Smith Y, Lindsley CW, Conn PJ, Xiang Z . M4 mAChR-mediated modulation of glutamatergic transmission at corticostriatal synapses . ACS Chem Neurosci . 5 . 4 . 318–24 . 2014 . 24528004 . 10.1021/cn500003z . 3990947.
  16. Huynh T, Valant C, Crosby IT, Sexton PM, Christopoulos A, Capuano B . Probing structural requirements of positive allosteric modulators of the M4 muscarinic receptor . J. Med. Chem. . 56 . 20 . 8196–200 . 2013 . 24074052 . 10.1021/jm401032k .
  17. Teaktong T, Piggott MA, Mckeith IG, Perry RH, Ballard CG, Perry EK . 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 . June 2005 . 15922057 . 10.1016/j.bbr.2005.02.019 . 34247659 .
  18. Web site: Muscarinic toxin 3 - Dendroaspis angusticeps (Eastern green mamba) .
  19. Lazareno S, Buckley NJ, Roberts FF . Characterization of muscarinic M4 binding sites in rabbit lung, chicken heart, and NG108-15 cells . Molecular Pharmacology . 38 . 6 . 805–15 . December 1990 . 2250662 .