Muscarinic acetylcholine receptor and 5-hydroxytryptamine receptor 4 (mAChR and 5-HT4R)

Muscarinic acetylcholine receptors (mAChRs) and 5-hydroxytryptamine receptor 4 (5-HT4R) are distinct classes of G protein-coupled receptors (GPCRs) that cooperatively regulate various physiological processes, most notably within the gastrointestinal (GI) and central nervous systems [StatPearls: Physiology, Muscarinic Receptor]. Muscarinic receptors, comprising five subtypes (M1-M5), are the primary mediators of acetylcholine signaling in the parasympathetic nervous system, controlling smooth muscle tone, heart rate, and glandular secretions [UniProt: P08172]. The 5-HT4 receptor is a serotonin receptor subtype that, upon activation, enhances the release of acetylcholine from enteric neurons, thereby indirectly stimulating muscarinic receptors to promote GI motility and peristalsis [IUPHAR/BPS: 5-HT4 receptor]. In the brain, both receptor systems are involved in cognitive functions, with 5-HT4 activation facilitating cholinergic transmission, making them relevant targets for treating Alzheimer's disease and other cognitive impairments [PubMed: 24555461]. Drugs targeting these receptors include 5-HT4 agonists like prucalopride for chronic constipation and muscarinic agonists or antagonists for conditions ranging from glaucoma to overactive bladder [PubMed: 11588351]. The interplay between these two targets is a cornerstone of prokinetic therapy, where 5-HT4-mediated acetylcholine release acts via muscarinic pathways to restore normal digestive transit.

Other names

Muscarinic receptors5-HT4 receptorsSerotonin 4 receptorsmAChRs5-HT4RMuscarinic cholinergic receptors

5-HT4 receptor agonists stimulate the release of acetylcholine from enteric neurons in the myenteric plexus; this released acetylcholine then binds to muscarinic receptors (primarily M3) on smooth muscle cells to induce contraction and promote gastrointestinal peristalsis [PubMed: 11588351].