Muscarinic acetylcholine receptor M4
# Muscarinic acetylcholine receptor M4

The muscarinic acetylcholine receptor $M_4,$ also known as the cholinergic receptor, muscarinic 4 (CHRM4), is a protein that, in humans, is encoded by the CHRM4 gene.

## Function

$M_4$ muscarinic receptors are coupled to $G_{i/o}$ heterotrimeric proteins.

They function as inhibitory autoreceptors for acetylcholine. Activation of $M_4$ receptors inhibits acetylcholine release in the striatum. The $M_2$ 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 $M_4$ receptors in the striatum inhibit $D_1-induced$ locomotor stimulation in mice. $M_4$ receptor-deficient mice exhibit increased locomotor simulation in response to $D_1$ agonists, amphetamine and cocaine. Neurotransmission in the striatum influences extrapyramidal motor control, thus alterations in $M_4$ activity may contribute to conditions such as Parkinson's disease.

## Ligands

### Orthosteric agonists

* acetylcholine
* carbachol
* oxotremorine

### Positive allosteric modulators

* LY-2033298
* VU-0152100 (ML-108)
* VU-0152099

### 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
* Himbacine
* Mamba toxin 3
* 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)
* Diphenhydramine
