Human muscarinic acetylcholine receptor M3 DREADD and Human muscarinic acetylcholine receptor M4 DREADD (hM3Dq and hM4Di)

hM3Dq and hM4Di are engineered G protein-coupled receptor (GPCR) constructs derived from the human M3 and M4 muscarinic acetylcholine receptors, respectively, and are the most widely used chemogenetic DREADDs (Designer Receptors Exclusively Activated by Designer Drugs). These receptors have been mutated so that they do not respond to endogenous acetylcholine but can be selectively activated by synthetic ligands, most commonly clozapine-N-oxide (CNO). hM3Dq (Gq-coupled) activation leads to neuronal excitation through calcium signaling, whereas hM4Di (Gi-coupled) induces neuronal inhibition via GIRK channel activation and hyperpolarization. DREADDs are powerful tools for non-invasively and reversibly controlling cellular activity in vivo and are widely used in neuroscience research to dissect neural circuits and behaviors. However, metabolic conversion of CNO to clozapine in many species is a key safety and interpretability concern. DREADDs are not therapeutic targets but are used to experimentally manipulate signaling pathways in biological models.

Other names

DREADD (Designer Receptor Exclusively Activated by Designer Drug)Gq-DREADD (for hM3Dq)Gi-DREADD (for hM4Di)Chemogenetic receptor (collective)hM3 muscarinic DREADD (hM3Dq)hM4 muscarinic DREADD (hM4Di)Human muscarinic DREADD

hM3Dq: Upon ligand (CNO/clozapine) binding, this receptor activates Gq signaling, leading to stimulation of phospholipase C, production of IP3/DAG, and increased intracellular calcium, resulting in cellular excitation. hM4Di: Upon ligand binding, this receptor activates Gi signaling, leading to inhibition of adenylate cyclase, decreased cAMP, activation of GIRK channels, hyperpolarization, and neuronal inhibition.