Human muscarinic acetylcholine receptor M4 (hM4Di) (hM4Di)

hM4Di is a synthetic, engineered G protein-coupled receptor (GPCR) derived from the human muscarinic acetylcholine receptor M4. It belongs to the class of Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) and is specifically modified to be insensitive to its natural ligand, acetylcholine, while remaining highly sensitive to biologically inert synthetic ligands like clozapine N-oxide (CNO) or deschloroclozapine (DCZ) [1, 7, 13]. Upon activation, hM4Di couples to the Gi signaling pathway, which inhibits adenylate cyclase, reduces cAMP levels, and activates G protein-coupled inwardly rectifying potassium (GIRK) channels [1, 5, 7]. This leads to membrane hyperpolarization and the suppression of presynaptic neurotransmitter release, effectively silencing neuronal activity [2, 11]. In therapeutic research, hM4Di is being explored as a tool for precision neuromodulation in conditions such as epilepsy, Parkinson's disease, chronic pain, and stroke [3, 6, 11]. Its ability to selectively inhibit specific neuronal populations makes it a promising candidate for gene-therapy-based interventions where localized control of hyperexcitability is required [6, 11].

Other names

hM4D(Gi)Gi-DREADDhM4DHuman M4 muscarinic DREADD

Agonist-induced activation of Gi-protein signaling, leading to inhibition of adenylate cyclase and activation of G protein-coupled inwardly rectifying potassium (GIRK) channels, resulting in neuronal hyperpolarization and inhibition of neurotransmitter release.