Citations to this article


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 ... Matthias Hebrok, Shaun R. Coughlin


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Citations to this article (60)

Title and authors Publication Year
Gα i/o -coupled receptor signaling restricts pancreatic β-cell expansion
M Berger, DW Scheel, H Macias, T Miyatsuka, H Kim, P Hoang, GM Ku, G Honig, A Liou, Y Tang, JB Regard, P Sharifnia, L Yu, J Wang, SR Coughlin, BR Conklin, ES Deneris, LH Tecott, MS German
Proceedings of the National Academy of Sciences 2015
Inverse Agonistic Action of 3-Iodothyronamine at the Human Trace Amine-Associated Receptor 5
J Dinter, J Mühlhaus, CL Wienchol, CX Yi, D Nürnberg, S Morin, A Grüters, J Köhrle, T Schöneberg, M Tschöp, H Krude, G Kleinau, H Biebermann, R Zhou
PloS one 2015
3-iodothyronamine differentially modulates  -2A-adrenergic receptor-mediated signaling
J Dinter, J Muhlhaus, SF Jacobi, CL Wienchol, M Coster, J Meister, CS Hoefig, A Muller, J Kohrle, A Gruters, H Krude, J Mittag, T Schoneberg, G Kleinau, H Biebermann
Journal of Molecular Endocrinology 2015
The GPCR, class C, group 6, subtype A (GPRC6A) receptor: from cloning to physiological function: The GPRC6A receptor
C Clemmensen, S Smajilovic, P Wellendorph, H Bräuner-Osborne
British Journal of Pharmacology 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
Uptake and metabolic effects of 3-iodothyronamine in hepatocytes
S Ghelardoni, G Chiellini, S Frascarelli, A Saba, R Zucchi
Journal of Endocrinology 2014
Evidence for the Gut Microbiota Short-Chain Fatty Acids as Key Pathophysiological Molecules Improving Diabetes
A Puddu, R Sanguineti, F Montecucco, GL Viviani
Mediators of Inflammation 2014
PKA enhances the acute insulin response leading to the restoration of glucose control
KA Kaihara, LM Dickson, JH Ellenbroek, CM Orr, BT Layden, B Wicksteed
Modulation of Gene Expression by 3-Iodothyronamine: Genetic Evidence for a Lipolytic Pattern
V Mariotti, E Melissari, C Iofrida, M Righi, MD Russo, R Donzelli, A Saba, S Frascarelli, G Chiellini, R Zucchi, S Pellegrini, GV Gnoni
PloS one 2014
Update on 3-iodothyronamine and its neurological and metabolic actions
R Zucchi, A Accorroni, G Chiellini
Frontiers in physiology 2014
CXCR4 and a cell-extrinsic mechanism control immature B lymphocyte egress from bone marrow
TC Beck, AC Gomes, JG Cyster, JP Pereira
Journal of Experimental Medicine 2014
Repurposing cAMP-Modulating Medications to Promote β-Cell Replication
Z Zhao, YS Low, NA Armstrong, JH Ryu, SA Sun, AC Arvanites, J Hollister-Lock, NH Shah, GC Weir, JP Annes
Molecular Endocrinology 2014
Insulin secretion stimulated by L-arginine and its metabolite L-ornithine depends on G i2
V Leiss, K Flockerzie, A Novakovic, M Rath, A Schonsiegel, L Birnbaumer, A Schurmann, C Harteneck, B Nurnberg
AJP Endocrinology and Metabolism 2014
MS Engelstoft, W Park, I Sakata, LV Kristensen, AS Husted, S Osborne-Lawrence, PK Piper, AK Walker, MH Pedersen, MK Nøhr, J Pan, CJ Sinz, PE Carrington, TE Akiyama, RM Jones, C Tang, K Ahmed, S Offermanns, KL Egerod, JM Zigman, TW Schwartz
Molecular Metabolism 2013
Elimination of von Hippel-Lindau function perturbs pancreas endocrine homeostasis in mice
S Puri, A García-Núñez, M Hebrok, DA Cano
PloS one 2013
Activation of Hedgehog signaling by loss of GNAS causes heterotopic ossification
JB Regard, D Malhotra, J Gvozdenovic-Jeremic, M Josey, M Chen, LS Weinstein, J Lu, EM Shore, FS Kaplan, Y Yang
Nature Medicine 2013
NMR-based metabolomics and breath studies show lipid and protein catabolism during low dose chronic T(1)AM treatment
JA Haviland, H Reiland, DE Butz, M Tonelli, WP Porter, R Zucchi, TS Scanlan, G Chiellini, FM Assadi-Porter
Obesity 2013
Pharmacological effects of 3-iodothyronamine (T1AM) in mice include facilitation of memory acquisition and retention and reduction of pain threshold
ME Manni, GD Siena, A Saba, M Marchini, E Landucci, E Gerace, M Zazzeri, C Musilli, D Pellegrini-Giampietro, R Matucci, R Zucchi, L Raimondi
British Journal of Pharmacology 2013
Minireview: Novel aspects of M3 muscarinic receptor signaling in pancreatic β-cells
K Nakajima, S Jain, IR de Azua, SM McMillin, M Rossi, J Wess
Molecular Endocrinology 2013
Effects of acute microinjections of the thyroid hormone derivative 3-iodothyronamine to the preoptic region of adult male rats on sleep, thermoregulation and motor activity
TD James, SX Moffett, TS Scanlan, JV Martin
Hormones and Behavior 2013
A β-Peptide Agonist of the GLP-1 Receptor, a Class B GPCR
EV Denton, CJ Craig, RL Pongratz, JS Appelbaum, AE Doerner, A Narayanan, GI Shulman, GW Cline, A Schepartz
Organic letters 2013
Probing heterotrimeric G protein activation: applications to biased ligands
C Denis, A Saulière, S Galandrin, JM Sénard, C Galés
Current pharmaceutical design 2012
GPRC6A mediates the effects of L-arginine on insulin secretion in mouse pancreatic islets
M Pi, Y Wu, NI Lenchik, I Gerling, LD Quarles
Endocrinology 2012
3-Iodothyronamine: a modulator of the hypothalamus-pancreas-thyroid axes in mice
ME Manni, GD Siena, A Saba, M Marchini, I Dicembrini, E Bigagli, L Cinci, M Lodovici, G Chiellini, R Zucchi, L Raimondi
British Journal of Pharmacology 2012
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
Endocrinology 2012