Human muscarinic acetylcholine receptor M4 designer receptor exclusively activated by designer drugs (hM4D(Gi))

The hM4D designer receptor exclusively activated by designer drugs (DREADD) is a synthetically engineered G protein-coupled receptor derived from the human muscarinic acetylcholine receptor M4 (Armbruster et al., 2007, PNAS). It has been modified via site-directed mutagenesis to lose its affinity for the endogenous neurotransmitter acetylcholine while gaining high sensitivity to otherwise inert designer ligands such as clozapine N-oxide (CNO) or deschloroclozapine (DCZ) (Nagai et al., 2020, Nature Communications). Upon activation by these ligands, hM4D couples to the Gi signaling pathway, leading to the inhibition of adenylyl cyclase and the activation of G protein-coupled inwardly-rectifying potassium (GIRK) channels (Roth, 2016, Neuron). This process results in cellular hyperpolarization and the subsequent silencing of neuronal activity (Urban and Roth, 2015, Annual Review of Pharmacology and Toxicology). In therapeutic contexts, hM4D is primarily explored for its potential to control hyperexcitable neuronal circuits in conditions like epilepsy and chronic pain. By using viral vectors to express hM4D in specific cell populations, researchers can achieve precise, reversible, and remote control over biological processes. This chemogenetic approach offers a significant advantage over traditional pharmacology by providing high spatial and temporal specificity. However, clinical translation requires careful consideration of ligand metabolism and the long-term safety of expressing foreign receptors in the human brain (Gomez et al., 2017, Science).

Other names

hM4DiGi-DREADDModified human M4 muscarinic receptorDREADD

Activation by a designer ligand triggers Gi-protein signaling, which inhibits adenylyl cyclase and opens potassium channels, leading to neuronal silencing (Roth, 2016, Neuron).