Designer receptor exclusively activated by designer drugs hM3Dq (hM3Dq) (hM3Dq)

The hM3Dq receptor is a synthetic G protein-coupled receptor (GPCR) engineered from the human M3 muscarinic receptor to be unresponsive to its natural ligand, acetylcholine, while remaining highly sensitive to otherwise inert designer drugs like clozapine N-oxide (CNO) (Armbruster et al., 2007, PNAS). As a member of the DREADD (Designer Receptors Exclusively Activated by Designer Drugs) family, hM3Dq is specifically coupled to the Gq signaling pathway (Roth, 2016, Neuron). Upon activation by a designer ligand, it triggers the phospholipase C cascade, increasing intracellular calcium and enhancing the excitability of the cells in which it is expressed (Alexander et al., 2009, Neuron). While primarily used as a powerful research tool in neuroscience to map and control neural circuits, hM3Dq is being investigated for therapeutic applications in gene therapy for conditions such as refractory epilepsy and Parkinson's disease (Lieb et al., 2019, Nature Medicine). In these contexts, the receptor is delivered to specific brain regions via viral vectors, allowing for precise, non-invasive control of neuronal activity through systemic drug administration. Challenges for clinical translation include the metabolic conversion of CNO to clozapine and the need for highly potent, brain-permeable designer ligands with minimal off-target effects (Gomez et al., 2017, Science). Recent developments have introduced more potent ligands like deschloroclozapine (DCZ) to improve the safety and efficacy of this chemogenetic system (Nagai et al., 2020, Nature Communications). Overall, hM3Dq represents a cornerstone of chemogenetic technology, bridging the gap between basic circuit research and potential precision medicine for neurological disorders.

Other names

hM3DqGq-DREADDModified human muscarinic acetylcholine receptor M3hM3D(Gq)

Activation of the Gq-protein signaling pathway, leading to phospholipase C activation, production of inositol trisphosphate (IP3), and subsequent release of intracellular calcium, resulting in increased neuronal excitability (Alexander et al., 2009, Neuron).