Muscarinic acetylcholine receptor M1 and Muscarinic acetylcholine receptor M2 (CHRM1/CHRM2)

Muscarinic acetylcholine receptors M1 and M2 are G protein-coupled receptors (GPCRs) that mediate the physiological effects of the neurotransmitter acetylcholine in the central and peripheral nervous systems (UniProt P11229, P08172). The M1 receptor is predominantly expressed in the cerebral cortex and hippocampus, where it plays a vital role in cognitive functions such as learning, memory, and attention by signaling through the Gq/11 pathway (StatPearls, NIH). In contrast, the M2 receptor is the primary muscarinic subtype in the heart, regulating heart rate and contractility via the Gi/o pathway, and also serves as a presynaptic autoreceptor in the brain (Wikipedia, NIH). These receptors are significant therapeutic targets; M1 agonists and positive allosteric modulators are being investigated for the treatment of cognitive symptoms in Alzheimer's disease and schizophrenia (BMS, PubMed). M2 receptors are targeted by antagonists like atropine to treat bradycardia and are involved in the side-effect profiles of many non-selective anticholinergic drugs (StatPearls). A major challenge in drug development is achieving subtype selectivity to avoid adverse effects, such as gastrointestinal distress from M1 activation or tachycardia from M2 blockade (NIH, PubMed). Furthermore, M1 and M2 receptors are involved in the regulation of smooth muscle contraction and glandular secretions, making them relevant in respiratory and gastrointestinal medicine (NIH). The structural similarity between the five muscarinic subtypes (M1-M5) complicates the design of ligands that do not cross-react, leading to a high incidence of off-target effects (PubMed). Recent research focuses on allosteric modulators to improve selectivity and reduce the risk of receptor desensitization (NIH). Overall, M1 and M2 receptors remain central to neuropharmacology and cardiovascular medicine due to their diverse and critical physiological roles.

Other names

Cholinergic receptor muscarinic 1Cholinergic receptor muscarinic 2M1RM2RHM1HM2Muscarinic acetylcholine receptor 1Muscarinic acetylcholine receptor 2

The M1 receptor is Gq-coupled, activating phospholipase C to increase inositol trisphosphate (IP3) and intracellular calcium; the M2 receptor is Gi-coupled, inhibiting adenylyl cyclase to decrease cAMP and activating G protein-coupled inwardly-rectifying potassium (GIRK) channels.