Muscarinic acetylcholine receptor M3, M4, and M5 (M3–M5 mAChR)

The muscarinic acetylcholine receptors M3, M4, and M5 are a subset of the five muscarinic receptor subtypes (M1–M5) belonging to the G protein-coupled receptor (GPCR) superfamily [10]. These receptors are essential for translating the signals of the neurotransmitter acetylcholine into diverse physiological responses across the central and peripheral nervous systems [2, 6]. The M3 and M5 subtypes are primarily coupled to Gq/11 proteins, which stimulate the phospholipase C pathway and increase intracellular calcium, whereas the M4 subtype is coupled to Gi/o proteins, which inhibit adenylyl cyclase and reduce cAMP levels [1, 5]. M3 receptors are widely distributed in peripheral tissues, where they mediate smooth muscle contraction in the lungs and bladder, as well as secretion from exocrine glands like the salivary and lacrimal glands [7, 15]. In contrast, M4 and M5 receptors are predominantly expressed in the brain; M4 is a key regulator of dopamine release in the striatum, making it a major target for antipsychotic and pro-cognitive therapies, while M5 is involved in the brain's reward circuitry and cerebral blood flow regulation [3, 11, 12]. Clinically, M3 antagonists are standard treatments for respiratory and urological disorders, while M4-selective agonists and allosteric modulators are currently being investigated for the treatment of schizophrenia and Alzheimer's disease [2, 13, 14].

Other names

CHRM3CHRM4CHRM5Muscarinic 3Muscarinic 4Muscarinic 5Cholinergic receptor muscarinic 3Cholinergic receptor muscarinic 4Cholinergic receptor muscarinic 5mAChR M3-M5

Competitive antagonism of M3 receptors to inhibit parasympathetic-mediated smooth muscle contraction and glandular secretion; Agonism or positive allosteric modulation (PAM) of M4 receptors to regulate dopaminergic neurotransmission; Modulation of Gq/11 (M3, M5) or Gi/o (M4) signaling pathways to alter intracellular second messenger levels.