Muscarinic acetylcholine receptor M4
Template:Infobox gene 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]
The M4 muscarinic receptor has been found to be a regulator of erythroid progenitor cell differentiation. Inhibition of the M4 muscarinic receptor provides therapeutic benefits in myelodysplastic syndrome and anemia.[10][11][12]
Ligands
Agonists
- Acetylcholine
- Carbachol
- CMI-936[13]
- NBI-1117568 (HTL-0016878)[14]
- ML-007[15]
- Oxotremorine
- Xanomeline
Positive allosteric modulators
- Emraclidine (CVL-231, PF-06852231)[16]
- LY-2033298[17][18]
- NS-136[19]
- SUVN-L3307032[20]
- VU-0152100 (ML-108)[21][22][23][24][25][26]
- VU-0152099[21]
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[27]
- Diphenhydramine
- Himbacine
- Mamba toxin 3[28]
- NBI-1076968[29]
- 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)[30]
- VU6028418
See also
References
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Further reading
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External links
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
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