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Abstract

The in vivo roles of the hundreds of mammalian G protein–coupled receptors (GPCRs) are incompletely understood. To explore these roles, we generated mice expressing the S1 subunit of pertussis toxin, a known inhibitor of Gi/o signaling, under the control of the ROSA26 locus in a Cre recombinase–dependent manner (ROSA26PTX). Crossing ROSA26PTX mice to mice expressing Cre in pancreatic β cells produced offspring with constitutive hyperinsulinemia, increased insulin secretion in response to glucose, and resistance to diet-induced hyperglycemia. This phenotype underscored the known importance of Gi/o and hence of GPCRs for regulating insulin secretion. Accordingly, we quantified mRNA for each of the approximately 373 nonodorant GPCRs in mouse to identify receptors highly expressed in islets and examined the role of several. We report that 3-iodothyronamine, a thyroid hormone metabolite, could negatively and positively regulate insulin secretion via the Gi-coupled α2A-adrenergic receptor and the Gs-coupled receptor Taar1, respectively, and protease-activated receptor–2 could negatively regulate insulin secretion and may contribute to physiological regulation of glucose metabolism. The ROSA26PTX system used in this study represents a new genetic tool to achieve tissue-specific signaling pathway modulation in vivo that can be applied to investigate the role of Gi/o-coupled GPCRs in multiple cell types and processes.

Authors

Jean B. Regard ... Matthias Hebrok, Shaun R. Coughlin

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Total citations by year in Crossref

Year: 2014 2012 2011 Total
Citations: 2 1 1 4
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Citations to this article in Crossref (4)

Title and authors Publication Year
Uptake and metabolic effects of 3-iodothyronamine in hepatocytes
S Ghelardoni, G Chiellini, S Frascarelli, A Saba, R Zucchi
Journal of Endocrinology 2014
Dynamin 2-dependent endocytosis is required for sustained S1PR1 signaling
T Willinger, SM Ferguson, JP Pereira, PD Camilli, RA Flavell
Journal of Experimental Medicine 2014
Distribution of exogenous [125I]-3-iodothyronamine in mouse in vivo: relationship with trace amine-associated receptors
G Chiellini, P Erba, V Carnicelli, C Manfredi, S Frascarelli, S Ghelardoni, G Mariani, R Zucchi
Journal of Endocrinology 2012
Cannabinoid receptor 2 positions and retains marginal zone B cells within the splenic marginal zone
JR Muppidi, TI Arnon, Y Bronevetsky, N Veerapen, M Tanaka, GS Besra, JG Cyster
Journal of Experimental Medicine 2011

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