A G Protein-Biased Designer G Protein-Coupled Receptor Useful for Studying the Physiological Relevance of Gq/11-Dependent Signaling Pathways Cell Biology

DREADDs (designer receptors exclusively activated by a designer drug) are CNO-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, CNO-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- vs. β-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 the present study, we report the development of a mutationally modified version of a non-biased DREADD derived from the M3 muscarinic receptor that can activate Gq/11 with high efficacy but lacks the ability to interact with β-arrestins. We also demonstrate that this novel DREADD is active in vivo and that cell type-selective expression of this new designer receptor can provide novel insights into the physiological roles of G protein (Gq/11)- vs. β-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 effects.

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from #Med Blogs by Alexandros G.Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/1VXvwtv
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