Muscarinic acetylcholine receptor M1 and Muscarinic acetylcholine receptor M4 (CHRM1/CHRM4)

Muscarinic acetylcholine receptors M1 and M4 are G protein-coupled receptors (GPCRs) predominantly expressed in the central nervous system, where they play critical roles in modulating neurotransmission, cognition, and motor control [1, 12]. The M1 receptor (CHRM1) is primarily located postsynaptically in the cerebral cortex and hippocampus, where its activation enhances synaptic plasticity and cognitive processes such as learning and memory [1, 10]. In contrast, the M4 receptor (CHRM4) acts as an inhibitory autoreceptor in the striatum, regulating the release of acetylcholine and indirectly modulating dopaminergic activity, which is essential for managing psychotic symptoms and motor functions [4, 9]. Dysregulation of these receptors is implicated in the pathophysiology of schizophrenia and Alzheimer's disease, particularly regarding cognitive impairment and psychosis [12, 18]. Xanomeline is a functionally selective agonist for both M1 and M4 receptors, designed to alleviate the positive, negative, and cognitive symptoms of schizophrenia without the side effects typical of dopamine D2 receptor antagonists [3, 13]. To mitigate peripheral cholinergic side effects like nausea and vomiting, xanomeline is often administered in combination with trospium chloride, a peripherally restricted muscarinic antagonist [1, 21].

Other names

CHRM1CHRM4M1 receptorM4 receptorM1RM4RCholinergic receptor muscarinic 1Cholinergic receptor muscarinic 4HM1HM4

Dual agonism of M1 and M4 muscarinic receptors; M1 activation enhances cognitive function and reduces negative symptoms, while M4 activation modulates dopaminergic signaling to alleviate positive symptoms of psychosis [1, 11, 18].