Human muscarinic acetylcholine receptor M4 designer receptor exclusively activated by designer drugs (hM4Di) (hM4Di)

hM4Di is a designer G protein-coupled receptor (GPCR) engineered from the human muscarinic acetylcholine receptor M4 (hM4) to be unresponsive to its endogenous ligand, acetylcholine, while becoming highly sensitive to synthetic "designer" ligands like clozapine N-oxide (CNO) or deschloroclozapine (DCZ) [2, 4]. It is the most widely used inhibitory chemogenetic tool in neuroscience, primarily utilized to silence specific neuronal populations with high spatial and temporal precision [9, 12]. Upon activation, hM4Di couples to the Gi/o signaling pathway, which inhibits adenylate cyclase and activates inwardly rectifying potassium channels, leading to cellular hyperpolarization and suppression of action potential firing [6, 8]. Beyond its role as a research tool, hM4Di is being investigated as a potential therapeutic for neurological disorders characterized by neuronal overactivity, such as focal epilepsy and chronic pain [1, 3]. However, challenges remain regarding the metabolic stability of its ligands and the potential for neurotoxicity or receptor desensitization during long-term expression [3, 4].

Other names

hM4D(Gi)Gi-DREADDInhibitory DREADDhM4DDesigner receptor exclusively activated by designer drugs M4

Activation of the Gi/o signaling pathway leading to inhibition of adenylate cyclase, reduction of cAMP, and activation of G-protein inwardly rectifying potassium (GIRK) channels, causing neuronal hyperpolarization and silencing [2, 4, 6, 8].