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Design and functional characterization of a novel, arrestin-biased designer G protein-coupled receptor

Thursday, October 11, 2012 — Poster Session IV

2:00 p.m. – 4:00 p.m.

Natcher Conference Center, Building 45




  • K Nakajima
  • J Wess


Recently, mutational modification of distinct muscarinic receptor subtypes has yielded novel designer G protein-coupled receptors (GPCRs) that are unable to bind acetylcholine, the endogenous muscarinic receptor ligand, but can be efficiently activated by clozapine-N-oxide (CNO), an otherwise pharmacologically inert compound. These CNO-sensitive designer GPCRs have emerged as powerful new tools to dissect the in vivo roles of distinct G protein signaling pathways in specific cell types or tissues. As is the case with other GPCRs, CNO-activated GPCRs do not only couple to heterotrimeric G proteins but can also recruit arrestin-2 and -3. Accumulating evidence suggests that arrestins can act as scaffolding proteins to promote G protein-independent signaling. In this study, we describe the development of an M3 muscarinic receptor-based designer receptor (Rq(R165L)) that is no longer able to couple to G proteins but can recruit arrestins and promote ERK1/2 phosphorylation in a CNO- and arrestin-dependent fashion. Moreover, CNO treatment of MIN6 insulinoma cells expressing the Rq(R165L) construct resulted in a robust, arrestin-dependent stimulation of insulin release, directly implicating arrestin signaling in the regulation of insulin release. This newly developed arrestin-biased designer GPCR represents an excellent novel tool to explore the physiological relevance of arrestin signaling pathways in distinct tissues.

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