Engineered inhibitory muscarinic acetylcholine receptor M4 (hM4Di) (hM4Di)

The engineered inhibitory DREADD (Designer Receptor Exclusively Activated by Designer Drugs) receptor, specifically the hM4Di variant, is a modified human muscarinic M4 receptor (CHRM4) engineered to lose affinity for its endogenous ligand, acetylcholine, while gaining high affinity for synthetic, otherwise inert designer ligands (Armbruster et al., 2007, PNAS). When expressed in the inhibitory neurons of the caudate nucleus—primarily GABAergic medium spiny neurons—this receptor serves as a chemogenetic tool to selectively and reversibly silence neuronal activity (Nagai et al., 2016, Nature Communications). Activation of hM4Di by ligands such as clozapine N-oxide (CNO) or the high-potency agonist deschloroclozapine (DCZ) induces the Gi protein-coupled signaling pathway, which inhibits adenylyl cyclase and opens G protein-coupled inwardly-rectifying potassium (GIRK) channels, leading to membrane hyperpolarization (Roth, 2016, Neuron). This targeted inhibition allows researchers and clinicians to modulate the basal ganglia circuitry, which is critical for motor control, habit formation, and reward-seeking behavior (Nagai et al., 2020, Nature Communications). Therapeutically, this approach is being explored for treating neurological and psychiatric conditions characterized by neuronal overactivity or circuit dysfunction, such as Parkinson's disease, dystonia, and drug addiction (Wess et al., 2013, Trends in Pharmacological Sciences). However, challenges remain regarding the metabolic conversion of CNO to clozapine in primates and the potential immunogenicity of the viral vectors used for receptor delivery (Gomez et al., 2017, Science).

Other names

hM4D(Gi)Inhibitory DREADDGi-DREADDDesigner receptor exclusively activated by designer drugs

Agonist-induced activation of the Gi signaling pathway, leading to the inhibition of adenylyl cyclase, reduction of cAMP levels, and activation of G protein-coupled inwardly-rectifying potassium (GIRK) channels, which results in neuronal hyperpolarization and suppression of action potential firing.