title: Insulin secretion stimulated by L-arginine and its metabolite L-ornithine depends on Gα(i2).
abstract: Bordetella pertussis toxin (PTx), also known as islet-activating protein, induces insulin secretion by ADP-ribosylation of inhibitory G proteins. PTx-induced insulin secretion may result either from inactivation of Gα(o) proteins or from combined inactivation of Gα(o), Gα(i1), Gα(i2), and Gα(i3) isoforms. However, the specific role of Gα(i2) in pancreatic β-cells still remains unknown. In global (Gα(i2)(-/-)) and β-cell-specific (Gα(i2)(βcko)) gene-targeted Gα(i2) mouse models, we studied glucose homeostasis and islet functions. Insulin secretion experiments and intracellular Ca²⁺ measurements were used to characterize Gα(i2) function in vitro. Gα(i2)(-/-) and Gα(i2)(βcko) mice showed an unexpected metabolic phenotype, i.e., significantly lower plasma insulin levels upon intraperitoneal glucose challenge in Gα(i2)(-/-) and Gα(i2)(βcko) mice, whereas plasma glucose concentrations were unchanged in Gα(i2)(-/-) but significantly increased in Gα(i2)(βcko) mice. These findings indicate a novel albeit unexpected role for Gα(i2) in the expression, turnover, and/or release of insulin from islets. Detection of insulin secretion in isolated islets did not show differences in response to high (16 mM) glucose concentrations between control and β-cell-specific Gα(i2)-deficient mice. In contrast, the two- to threefold increase in insulin secretion evoked by L-arginine or L-ornithine (in the presence of 16 mM glucose) was significantly reduced in islets lacking Gα(i2). In accord with a reduced level of insulin secretion, intracellular calcium concentrations induced by the agonistic amino acid L-arginine did not reach control levels in β-cells. The presented analysis of gene-targeted mice provides novel insights in the role of β-cell Gα(i2) showing that amino acid-induced insulin-release depends on Gα(i2).
authors.affiliation: Department of Pharmacology and Experimental Therapy, Institute of Experimental and Clinical Pharmacology and Toxicology, Eberhard Karls University Hospitals and Clinics, and Interfaculty Center of Pharmacogenomics and Drug Research, University of Tübingen, Tübingen, Germany;
authors.forename: Veronika
authors.initials: V
authors.lastname: Leiss
authors.affiliation: Department of Pharmacology and Experimental Therapy, Institute of Experimental and Clinical Pharmacology and Toxicology, Eberhard Karls University Hospitals and Clinics, and Interfaculty Center of Pharmacogenomics and Drug Research, University of Tübingen, Tübingen, Germany;
authors.forename: Katarina
authors.initials: K
authors.lastname: Flockerzie
authors.affiliation: Department of Pharmacology and Experimental Therapy, Institute of Experimental and Clinical Pharmacology and Toxicology, Eberhard Karls University Hospitals and Clinics, and Interfaculty Center of Pharmacogenomics and Drug Research, University of Tübingen, Tübingen, Germany;
authors.forename: Ana
authors.initials: A
authors.lastname: Novakovic
authors.affiliation: Department of Experimental Diabetology, German Institute of Human Nutrition, Potsdam-Rehbrücke, Nuthetal, Germany;
authors.forename: Michaela
authors.initials: M
authors.lastname: Rath
authors.affiliation: Department of Pharmacology and Experimental Therapy, Institute of Experimental and Clinical Pharmacology and Toxicology, Eberhard Karls University Hospitals and Clinics, and Interfaculty Center of Pharmacogenomics and Drug Research, University of Tübingen, Tübingen, Germany;
authors.forename: Annika
authors.initials: A
authors.lastname: Schönsiegel
authors.affiliation: Laboratory of Neurobiology, National Institute of Environmental Health Sciences, National Institutes of Health/Department of Health and Human Services, Durham, North Carolina.
authors.forename: Lutz
authors.initials: L
authors.lastname: Birnbaumer
authors.affiliation: Department of Experimental Diabetology, German Institute of Human Nutrition, Potsdam-Rehbrücke, Nuthetal, Germany;
authors.forename: Annette
authors.initials: A
authors.lastname: Schürmann
authors.affiliation: Department of Pharmacology and Experimental Therapy, Institute of Experimental and Clinical Pharmacology and Toxicology, Eberhard Karls University Hospitals and Clinics, and Interfaculty Center of Pharmacogenomics and Drug Research, University of Tübingen, Tübingen, Germany;
authors.forename: Christian
authors.initials: C
authors.lastname: Harteneck
authors.affiliation: Department of Pharmacology and Experimental Therapy, Institute of Experimental and Clinical Pharmacology and Toxicology, Eberhard Karls University Hospitals and Clinics, and Interfaculty Center of Pharmacogenomics and Drug Research, University of Tübingen, Tübingen, Germany; bernd.nuernberg@uni-tuebingen.de.
authors.forename: Bernd
authors.initials: B
authors.lastname: Nürnberg
mesh_terms: D000818:Animals; D001120:Arginine / Q000378:metabolism*; D001786:Blood Glucose / Q000032:analysis; D020013:Calcium Signaling; D003433:Crosses, Genetic; D015536:Down-Regulation; D005455:Fluorescent Antibody Technique; D051960:GTP-Binding Protein alpha Subunit, Gi2 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D006943:Hyperglycemia / Q000097:blood / Q000378:metabolism / Q000517:prevention & control*; D007003:Hypoglycemia / Q000097:blood / Q000378:metabolism / Q000517:prevention & control; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009952:Ornithine / Q000097:blood / Q000378:metabolism*; D013047:Specific Pathogen-Free Organisms; D046509:Tissue Culture Techniques; D015854:Up-Regulation
chemical_list: D001786:Blood Glucose; D007328:Insulin; D001120:Arginine; D009952:Ornithine; C000594262:GNAO1 protein, mouse; D051960:GTP-Binding Protein alpha Subunit, Gi2; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; C498016:Gnai2 protein, mouse
keywords: GPCR; Gαi2; insulin secretion; l-arginine; β-cell