Muscarinic acetylcholine receptor M1 (CHRM1) (CHRM1)

The Muscarinic acetylcholine receptor M1 (CHRM1) is a Class A G protein-coupled receptor predominantly expressed in the forebrain, including the cortex, hippocampus, and striatum (UniProt P11229). It serves as a key mediator of cholinergic neurotransmission, primarily signaling through the Gq/11 heterotrimeric G proteins to activate phospholipase C, which results in increased intracellular calcium and modulated neuronal excitability (PubMed: 28934319). CHRM1 is a high-priority therapeutic target for neurodegenerative and neuropsychiatric disorders, such as Alzheimer's disease and schizophrenia, because of its fundamental role in cognitive processes like learning, memory, and attention (PubMed: 33037116). Pharmacological intervention typically aims to enhance M1 signaling using orthosteric agonists or positive allosteric modulators (PAMs) to alleviate cognitive deficits (PubMed: 34615486). However, achieving subtype selectivity remains a significant challenge; non-selective activation often leads to dose-limiting peripheral side effects, such as gastrointestinal distress and excessive sweating, due to cross-reactivity with M2 and M3 receptors (PubMed: 30103115). Recent clinical strategies, such as the combination of the agonist xanomeline with the peripheral antagonist trospium (KarXT), have been developed to mitigate these adverse events while maintaining central efficacy (PubMed: 34615486). Additionally, the development of highly selective M1 PAMs offers a way to fine-tune cholinergic signaling by enhancing the effect of endogenous acetylcholine only when and where it is released (PubMed: 30103115). Overall, the M1 receptor remains one of the most promising targets for restoring cognitive function in patients with cholinergic system dysfunction.

Other names

CHRM1Muscarinic acetylcholine receptor M1M1 muscarinic receptorCholinergic receptor muscarinic 1M1R

Agonism of the Gq-coupled signaling pathway to enhance cognitive function; Positive allosteric modulation to increase sensitivity to endogenous acetylcholine; Antagonism to block cholinergic signaling in specific clinical contexts (PubMed: 30103115).