Muscarinic acetylcholine receptor M4

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.^[5][6]

CHRM4
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 5DSG
Identifiers
Aliases	CHRM4, HM4, M4R, cholinergic receptor muscarinic 4
External IDs	OMIM: 118495; MGI: 88399; HomoloGene: 20192; GeneCards: CHRM4; OMA:CHRM4 - orthologs
Gene location (Human) Chr. Chromosome 11 (human)[1] Band 11p11.2 Start 46,383,789 bp[1] End 46,391,776 bp[1]
Gene location (Mouse) Chr. Chromosome 2 (mouse)[2] Band 2 E1|2 50.63 cM Start 91,757,594 bp[2] End 91,759,033 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in testicle caudate nucleus putamen nucleus accumbens right frontal lobe spleen prefrontal cortex anterior cingulate cortex Brodmann area 9 left testis Top expressed in superior frontal gyrus primary visual cortex dentate gyrus of hippocampal formation granule cell embryo pretectal area embryo spermatid secondary oocyte zygote meninges More reference expression data BioGPS n/a
Gene ontology Molecular function G protein-coupled receptor activity signal transducer activity G protein-coupled acetylcholine receptor activity G protein-coupled serotonin receptor activity neurotransmitter receptor activity Cellular component integral component of membrane postsynaptic membrane membrane plasma membrane synapse integral component of plasma membrane cell junction dendrite Biological process G protein-coupled acetylcholine receptor signaling pathway regulation of locomotion synaptic transmission, cholinergic 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 cell population proliferation signal transduction G protein-coupled receptor signaling pathway G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger chemical synaptic transmission G protein-coupled serotonin receptor signaling pathway Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 1132 12672 Ensembl ENSG00000180720 ENSMUSG00000040495 UniProt P08173 P32211 RefSeq (mRNA) NM_000741 NM_001366692 NM_007699 RefSeq (protein) NP_000732 NP_001353621 NP_031725 Location (UCSC) Chr 11: 46.38 – 46.39 Mb Chr 2: 91.76 – 91.76 Mb PubMed search [3] [4]
Wikidata
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Function

M₄ muscarinic receptors are coupled to G_i/o heterotrimeric proteins.^[7]

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.^[8][9][10] Neurotransmission in the striatum influences extrapyramidal motor control, thus alterations in M₄ activity may contribute to conditions such as Parkinson's disease.^[11][12][13]

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.^[14][15][16]

Ligands

Agonists

• Acetylcholine
• Carbachol
• CMI-936^[17]
• NBI-1117568 (HTL-0016878)^[18]
• ML-007^[19]
• Oxotremorine
• Xanomeline

Positive allosteric modulators

• Emraclidine (CVL-231, PF-06852231)^[20]
• LY-2033298^[21][22]
• NS-136^[23]
• SUVN-L3307032^[24]
• VU-0152100 (ML-108)^{[25][26][27][28][29][30]}
• VU-0152099^[25]

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^[31]
• Diphenhydramine
• Himbacine
• Mamba toxin 3^[32]
• NBI-1076968^[33]
• 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)^[34]
• VU6028418

See also

• Muscarinic acetylcholine receptor