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.
Jean B. Regard, Hiroshi Kataoka, David A. Cano, Eric Camerer, Liya Yin, Yao-Wu Zheng, Thomas S. Scanlan, Matthias Hebrok, Shaun R. Coughlin
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Biosynthesis of 3-Iodothyronamine (T1AM) Is Dependent on the Sodium-Iodide Symporter and Thyroperoxidase but Does Not Involve Extrathyroidal Metabolism of T4
SA Hackenmueller, M Marchini, A Saba, R Zucchi, TS Scanlan |
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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
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The Journal of biological chemistry | 2011 |
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Journal of Clinical Investigation | 2010 |
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Proceedings of the National Academy of Sciences | 2010 |
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Diabetes | 2010 |
Sphingosine-1-phosphate in the plasma compartment regulates basal and inflammation-induced vascular leak
Eric Camerer, Jean B. Regard, Ivo Cornelissen, Yoga Srinivasan, Daniel N. Duong, Daniel Palmer, Trung H. Pham, Jinny S. Wong, Rajita Pappu and Shaun R. Coughlin |
Journal of Clinical Investigation | 2009 |
A chemical-genetic approach to study G protein regulation of cell function in vivo
JM Guettier, D Gautam, M Scarselli, IR de Azua, JH Li, E Rosemond, X Ma, FJ Gonzalez, BN Armbruster, H Lu, BL Roth, J Wess |
Proceedings of the National Academy of Sciences | 2009 |
G(i)-coupled GPCR signaling controls the formation and organization of human pluripotent colonies
K Nakamura, N Salomonis, K Tomoda, S Yamanaka, BR Conklin |
PloS one | 2009 |
The selective antagonist EPPTB reveals TAAR1-mediated regulatory mechanisms in dopaminergic neurons of the mesolimbic system
A Bradaia, G Trube, H Stalder, RD Norcross, L Ozmen, JG Wettstein, A Pinard, D Buchy, M Gassmann, MC Hoener, B Bettler |
Proceedings of the National Academy of Sciences | 2009 |
International Union of Pharmacology. LXXII. Recommendations for trace amine receptor nomenclature
JJ Maguire, WA Parker, SM Foord, TI Bonner, RR Neubig, AP Davenport |
Pharmacological reviews | 2009 |
The molecular basis of species-specific ligand activation of trace amine-associated receptor 1 (TAAR(1))
ES Tan, JC Naylor, ES Groban, JR Bunzow, MP Jacobson, DK Grandy, TS Scanlan |
ACS chemical biology | 2009 |
Islet G protein-coupled receptors as potential targets for treatment of type 2 diabetes
B Ahrén |
Nature Reviews Drug Discovery | 2009 |
Iodothyronamines are oxidatively deaminated to iodothyroacetic acids in vivo
WJ Wood, T Geraci, A Nilsen, AE DeBarber, TS Scanlan |
Chembiochem : a European journal of chemical biology | 2009 |
Identification of a transient subpial neurogenic zone in the developing dentate gyrus and its regulation by Cxcl12 and reelin signaling
G Li, H Kataoka, SR Coughlin, SJ Pleasure |
Development (Cambridge, England) | 2009 |
Anatomical Profiling of G Protein-Coupled Receptor Expression
JB Regard, IT Sato, SR Coughlin |
Cell | 2008 |
The Role of Vasoactive Intestinal Peptide (VIP) in Megakaryocyte Proliferation
C Nam, AJ Case, BS Hostager, MS O’Dorisio |
Journal of Molecular Neuroscience | 2008 |
Cardiac effects of thyronamines
R Zucchi, S Ghelardoni, G Chiellini |
Heart Failure Reviews | 2008 |
3-Iodothyronamine (T1AM): A New Player on the Thyroid Endocrine Team?
TS Scanlan |
Endocrinology | 2008 |
A Role for von Hippel-Lindau Protein in Pancreatic -Cell Function
S Puri, DA Cano, M Hebrok |
Diabetes | 2008 |
Identification and characterization of 3-iodothyronamine intracellular transport
AG Ianculescu, KM Giacomini, TS Scanlan |
Endocrinology | 2008 |
Validation of a liquid chromatography-tandem mass spectrometry method to enable quantification of 3-iodothyronamine from serum
AE DeBarber, T Geraci, VP Colasurdo, SA Hackenmueller, TS Scanlan |
Journal of chromatography. A | 2008 |