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A G Protein-biased Designer G Protein-coupled Receptor Useful for Studying the Physiological Relevance of Gq/11-dependent Signaling Pathways.

Hu J, Stern M, Gimenez LE, Wanka L, Zhu L, Rossi M, Meister J, Inoue A, Beck-Sickinger AG, Gurevich VV, Wess J
J Biol Chem. 2016 291 (15): 7809-20

PMID: 26851281 · PMCID: PMC4824988 · DOI:10.1074/jbc.M115.702282

Designerreceptorsexclusivelyactivated by adesignerdrug (DREADDs) are clozapine-N-oxide-sensitive designer G protein-coupled receptors (GPCRs) that have emerged as powerful novel chemogenetic tools to study the physiological relevance of GPCR signaling pathways in specific cell types or tissues. Like endogenous GPCRs, clozapine-N-oxide-activated DREADDs do not only activate heterotrimeric G proteins but can also trigger β-arrestin-dependent (G protein-independent) signaling. To dissect the relative physiological relevance of G protein-mediatedversusβ-arrestin-mediated signaling in different cell types or physiological processes, the availability of G protein- and β-arrestin-biased DREADDs would be highly desirable. In this study, we report the development of a mutationally modified version of a non-biased DREADD derived from the M3muscarinic receptor that can activate Gq/11with high efficacy but lacks the ability to interact with β-arrestins. We also demonstrate that this novel DREADD is activein vivoand that cell type-selective expression of this new designer receptor can provide novel insights into the physiological roles of G protein (Gq/11)-dependentversusβ-arrestin-dependent signaling in hepatocytes. Thus, this novel Gq/11-biased DREADD represents a powerful new tool to study the physiological relevance of Gq/11-dependent signaling in distinct tissues and cell types, in the absence of β-arrestin-mediated cellular effects. Such studies should guide the development of novel classes of functionally biased ligands that show high efficacy in various pathophysiological conditions but display a reduced incidence of side effects.

© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

MeSH Terms (18)

Animals Arrestins beta-Arrestins Calcium Cells, Cultured Chlorocebus aethiops COS Cells Gene Knockdown Techniques Glucose GTP-Binding Protein alpha Subunits, Gq-G11 HEK293 Cells Hepatocytes Humans Mice, Inbred C57BL Protein Interaction Mapping Protein Interaction Maps Receptors, G-Protein-Coupled Signal Transduction

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