A G protein-biased designer G protein-coupled receptor useful for studying the physiological relevance of Gq/11-dependent signaling pathways

Jianxin Hu, Matthew Stern, Luis E. Gimenez, Lizzy Wanka, Lu Zhu, Mario Rossi, Jaroslawna Meister, Asuka Inoue, Annette G. Beck-Sickinger, Vsevolod V. Gurevich, Jürgen Wess

Research output: Contribution to journalArticlepeer-review

16 Citations (Scopus)


Designer receptors exclusively activated by a designer drug (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-mediated versus β-arrestin-mediated signaling in different cell types or physiological processes, the availability of G proteinand 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/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)-dependent versus 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 side effects.

Original languageEnglish
Pages (from-to)7809-7820
Number of pages12
JournalJournal of Biological Chemistry
Issue number15
Publication statusPublished - 2016 Apr 8

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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