Human M3 muscarinic designer receptor exclusively activated by designer drugs (hM3Dq) (hM3Dq)

The Human M3 muscarinic designer receptor exclusively activated by designer drugs (hM3Dq) is an engineered G protein-coupled receptor (GPCR) that serves as a cornerstone in the field of chemogenetics (Armbruster et al., 2007, PNAS). It is derived from the human M3 muscarinic receptor through two specific point mutations, Y149C and A239G, which eliminate its responsiveness to the endogenous neurotransmitter acetylcholine while creating high affinity for otherwise inert ligands like clozapine N-oxide (CNO) and deschloroclozapine (DCZ) (Roth, 2016, Neuron; Nagai et al., 2020, Nature Communications). Upon binding of a designer ligand, hM3Dq activates the Gq-alpha signaling pathway, triggering phospholipase C, increasing intracellular calcium levels, and ultimately enhancing neuronal excitability and firing rates. This system allows for the remote, non-invasive, and reversible control of specific neural circuits with high temporal and spatial precision. While primarily used as a research tool to map brain function, hM3Dq is also being investigated for therapeutic applications, particularly in gene therapy for refractory focal epilepsy and other neurological disorders (Lieb et al., 2019, Nature Medicine). The ability to modulate specific cell populations on demand offers a significant advantage over traditional pharmacological interventions that often lack cellular specificity. However, challenges remain regarding the metabolic stability of ligands like CNO and the potential for off-target effects at high concentrations.

Other names

hM3DM3-DREADDGq-DREADDhM3D(Gq)Designer receptor exclusively activated by designer drugs

The receptor acts as a chemogenetic actuator that, upon binding of a designer ligand such as clozapine N-oxide or deschloroclozapine, activates the Gq-alpha signaling cascade. This leads to the activation of phospholipase C, the production of inositol trisphosphate (IP3), and the subsequent release of calcium from the endoplasmic reticulum, resulting in increased neuronal excitability and burst firing.