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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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Citations to this article in year 2011 (7)

Title and authors Publication Year
Augmented glucose-induced insulin release in mice lacking Go2, but not Go1 or Gi proteins
Y Wang, S Park, NS Bajpayee, Y Nagaoka, G Boulay, L Birnbaumer, M Jiang
Proceedings of the National Academy of Sciences 2011
Cannabinoids Inhibit Insulin Receptor Signaling in Pancreatic β-Cells
W Kim, ME Doyle, Z Liu, Q Lao, YK Shin, OD Carlson, HS Kim, S Thomas, JK Napora, EK Lee, R Moaddel, Y Wang, S Maudsley, B Martin, RN Kulkarni, JM Egan
Diabetes 2011
G Protein-Coupled Receptor Signaling and Sphingosine-1-Phosphate Play a Phylogenetically Conserved Role in Endocrine Pancreas Morphogenesis ▿
I Serafimidis, S Heximer, D Beis, A Gavalas
Molecular and cellular biology 2011
Blockade of Receptor-Activated Gi Signaling in Osteoblasts In Vivo Leads to Site-Specific Increases in Cortical and Cancellous Bone Formation
SM Millard, AM Louie, L Wattanachanya, TJ Wronski, BR Conklin, RA Nissenson
Journal of Bone and Mineral Research 2011
CXCR4 and CXCR7 Have Distinct Functions in Regulating Interneuron Migration
Y Wang, G Li, A Stanco, JE Long, D Crawford, GB Potter, SJ Pleasure, T Behrens, JL Rubenstein
Neuron 2011
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
ApoB-100-containing lipoproteins are major carriers of 3-iodothyronamine in circulation
G Roy, E Placzek, TS Scanlan
The Journal of biological chemistry 2011

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