Arrestin-biased muscarinic acetylcholine receptor DREADD (hM3D-arr)

Arrestin-biased muscarinic DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) are engineered G protein-coupled receptors (GPCRs) designed to signal exclusively through beta-arrestin pathways rather than traditional G-protein pathways (Nakajima & Wess, 2012). These receptors, most notably the hM3D-arr (or Rq(R165A)) variant, are derived from the human M3 muscarinic receptor through site-directed mutagenesis that abolishes G-protein coupling while preserving arrestin recruitment (Wess et al., 2013). They are activated by otherwise pharmacologically inert ligands such as clozapine N-oxide (CNO) or deschloroclozapine (DCZ), allowing for precise chemogenetic control over arrestin-dependent cellular processes (Roth, 2016). In research settings, these tools are used to dissect the specific roles of arrestin signaling in complex biological systems, including its impact on synaptic plasticity, insulin secretion, and thermogenesis (Bonaventura et al., 2019). By isolating arrestin-mediated effects, such as MAPK/ERK activation and receptor internalization, these DREADDs help identify potential therapeutic strategies for neurological and metabolic disorders where biased signaling is relevant. They represent a critical advancement in the study of GPCR functional selectivity and the development of biased agonists.

Other names

Rq(R165A)Arrestin-biased M3 DREADDhM3D-arrArrestin-biased Designer Receptor Exclusively Activated by Designer Drugs

Selective activation by designer ligands (e.g., CNO) triggers beta-arrestin recruitment and downstream arrestin-mediated signaling pathways, such as ERK1/2 phosphorylation, in the absence of G-protein activation (Nakajima & Wess, 2012).