Muscarinic acetylcholine receptor M3 (M3R) (M3R)

The Muscarinic acetylcholine receptor M3 (M3R) is a key member of the G protein-coupled receptor (GPCR) superfamily, specifically the Class A family, and is encoded by the CHRM3 gene [UniProt, PubMed]. It is widely distributed throughout the body, with high expression in the smooth muscles of the airways, gastrointestinal tract, and bladder, as well as in exocrine glands such as the salivary and lacrimal glands [Wikipedia, PubMed]. The primary biological function of the M3R is to mediate the parasympathetic 'rest and digest' response; its activation triggers the Gq/11 signaling pathway, leading to increased intracellular calcium that causes smooth muscle contraction and glandular secretion [StatPearls, PubMed]. In disease states, M3R overactivity contributes to the pathophysiology of chronic obstructive pulmonary disease (COPD), asthma, and overactive bladder, while its role in the pancreas is critical for glucose-stimulated insulin secretion [PubMed, NIH]. Clinically, M3R is a major therapeutic target; antagonists like tiotropium and oxybutynin are used to manage respiratory and urinary disorders by blocking acetylcholine-induced contractions [IUPHAR, StatPearls]. Conversely, agonists such as pilocarpine are employed to treat xerostomia in Sjögren's syndrome and to lower intraocular pressure in glaucoma [StatPearls, PubMed]. A significant challenge in drug development is the high structural conservation of the orthosteric binding site across muscarinic subtypes, which often results in off-target effects like dry mouth, constipation, and cognitive impairment [PubMed, NIH]. Recent research focuses on allosteric modulators to achieve better subtype selectivity and reduce these systemic safety concerns [PubMed].

Other names

CHRM3Muscarinic 3HM3Cholinergic receptor muscarinic 3EGBRS

Drugs targeting the M3 muscarinic receptor act as either agonists or antagonists. Agonists mimic acetylcholine by binding to the receptor and activating the Gq/11 protein-coupled pathway, which stimulates phospholipase C, increases inositol trisphosphate (IP3), and raises intracellular calcium levels to induce smooth muscle contraction and glandular secretion [StatPearls, PubMed]. Antagonists (anticholinergics) competitively inhibit the binding of acetylcholine to the M3 receptor, thereby preventing these excitatory effects and promoting smooth muscle relaxation, which is therapeutic in conditions like COPD and overactive bladder [IUPHAR, PubMed].