Human muscarinic acetylcholine receptor M1 (hM1Dq) (hM1Dq)

hM1Dq is a Designer Receptor Exclusively Activated by Designer Drugs (DREADD) engineered from the human muscarinic acetylcholine receptor M1. Through site-directed mutagenesis (specifically Y106C and A196G), the receptor is rendered insensitive to its endogenous ligand, acetylcholine, but gains high affinity for synthetic ligands such as clozapine N-oxide (CNO) and deschloroclozapine (DCZ) [1, 2]. Upon activation by these designer drugs, hM1Dq selectively couples to the Gq-protein signaling pathway, which stimulates phospholipase C and increases intracellular calcium, leading to neuronal excitation and increased firing [1, 8]. This chemogenetic tool allows researchers to remotely and non-invasively control the activity of specific neural circuits with high spatial and temporal precision [4, 10]. While currently used primarily in preclinical research to study behaviors and disease mechanisms, hM1Dq and other DREADDs are being explored for potential therapeutic applications in gene therapy for conditions like epilepsy and Parkinson's disease [6, 7]. Key challenges include the metabolic conversion of CNO to clozapine, which can cause off-target effects, and the potential for receptor desensitization during chronic treatment [9, 6].

Other names

hM1DqhM1Dq DREADDM1-DREADDGq-DREADDDesigner receptor exclusively activated by designer drugs based on M1

Agonist binding to the engineered receptor triggers Gq-protein coupling, which activates phospholipase C (PLC). This leads to the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) into inositol trisphosphate (IP3) and diacylglycerol (DAG). IP3 induces the release of calcium from intracellular stores, while DAG activates protein kinase C, collectively resulting in neuronal depolarization and increased firing rates.