Human muscarinic acetylcholine receptor M4 DREADD (hM4Di)

The hM4Di receptor is a chemogenetic tool, specifically a Designer Receptor Exclusively Activated by Designer Drugs (DREADD), engineered from the human M4 muscarinic acetylcholine receptor (Roth, 2016; Armbruster et al., 2007). It has been modified via directed evolution to lose its affinity for the endogenous ligand acetylcholine and instead gain high potency for otherwise inert designer ligands such as clozapine N-oxide (CNO) or deschloroclozapine (DCZ) (Armbruster et al., 2007; Nagai et al., 2020). Upon activation, hM4Di couples to the Gi/o signaling pathway, which inhibits adenylyl cyclase and activates G protein-coupled inwardly-rectifying potassium (GIRK) channels, leading to cellular hyperpolarization and the suppression of neuronal activity (Roth, 2016; Urban & Roth, 2015). This receptor is widely utilized in neuroscience research to selectively and reversibly silence specific neuronal populations in vivo (Urban & Roth, 2015). Beyond basic research, hM4Di is being investigated as a potential gene therapy component for treating neurological conditions characterized by neuronal overactivity, such as focal epilepsy and chronic pain (Roth, 2016; Gomez et al., 2017). Its therapeutic application relies on the precise delivery of the receptor gene to target cells via viral vectors, followed by systemic administration of the designer ligand to modulate the circuit (Roth, 2016; Nagai et al., 2020).

Other names

hM4D(Gi)Gi-DREADDInhibitory DREADDDesigner receptor exclusively activated by designer drugs hM4Di

Activation of the Gi/o protein-coupled pathway leading to inhibition of adenylyl cyclase and activation of G protein-coupled inwardly-rectifying potassium (GIRK) channels, resulting in membrane hyperpolarization and suppression of neuronal firing.