Insulin secretion stimulated by l-arginine and its metabolite l-ornithine depends on Gα_i2

Abstract

detella 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 G␣o proteins or from combined inactivation of G␣o, G␣i1, G␣i2, and G␣i3 isoforms. However, the specific role of G␣i2 in pancreatic ␤-cells still remains unknown. In global (G␣i2 Ϫ/Ϫ ) and ␤-cell-specific (G␣ i2 ␤cko ) gene-targeted G␣i2 mouse models, we studied glucose homeostasis and islet functions. Insulin secretion experiments and intracellular Ca 2ϩ measurements were used to characterize G␣i2 function in vitro. G␣i2Ϫ/Ϫ and G␣i2 ␤cko mice showed an unexpected metabolic phenotype, i.e., significantly lower plasma insulin levels upon intraperitoneal glucose challenge in G␣i2 Ϫ/Ϫ and G␣i2 ␤cko mice, whereas plasma glucose concentrations were unchanged in G␣ i2 Ϫ/Ϫ but significantly increased in G␣i2 ␤cko mice. These findings indicate a novel albeit unexpected role for G␣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 ␤-cellspecific G␣ 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 G␣ 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 ␤-cells. The presented analysis of gene-targeted mice provides novel insights in the role of ␤-cell G␣ i2 showing that amino acid-induced insulin-release depends on G␣i2. G␣ i2; insulin secretion; ␤-cell; L-arginine; GPCR GLUCOSE IS THE PRINCIPAL STIMULATOR of insulin secretion from pancreatic ␤-cells. Together with regulators such as other nutrients or hormones, it adjusts insulin secretion according to physiological demands. A disruption of this tightly controlled process can lead to diabetes mellitus and its comorbidities. Physiological regulators of insulin release include not only glucose but also other nutrients such as free fatty acids or amino acids on the one hand, and hormones including glucagon and norepinephrine on the other hand. They all have in common that they signal via seven-transmembrane G proteincoupled receptors (GPCR) present on the surface of pancreatic ␤-cells (1, 28, 33). Upon ligand binding, GPCRs activate heterotrimeric G proteins, thereby modulating the activity of cellular effectors. It is widely accepted that insulin release from pancreatic ␤-cells can be triggered via G␣ s -and/or G q /G 11 -dependent mechanisms (2, 41). Studies in isolated systems and in animals, using pertussis toxin (PTx), also known as isletactivating protein, suggest G␣ i /G␣ o -dependent signaling as being important for inhibition of insulin secretion (11,14,15). PTx specifically catalyzes the ADP-ribosylation of a cysteine residue locat...

Gαi Proteins are Indispensable for Hearing

“…A specific deletion of Gnai3 or Gnai2 in the inner ear and telencephalon was achieved by crossing Gnai3 fl/fl or Gnai2 fl/fl mice and Foxg1-Cre mice. Gnai2 fl/fl mice were provided by the Comparative Medicine Branch of the National Institute of Environmental Health Sciences, North Carolina 27709 [25], backcrossed on a C57BL/6N background [26], and the FoxG1-Cre mouse line [27] was purchased from The Jackson Laboratory (Bar Harbor, ME, USA), on a C57BL/6N background. A tissue-specific mutant mouse line was generated where both Gnai genes were disrupted by crossing with the FoxG1-Cre mouse line.…”

“…Subsequently, the mouse strains were backcrossed on a C57BL/6N background for at least nine generations [26,29]. The Gnai2 mutant mouse line was kept in Individually Ventilated Cages (IVC), while the Gnai3 mutant mouse line was kept under SPF conditions.…”

Platelet G i protein Gα i2 is an essential mediator of thrombo-inflammatory organ damage in mice

“…Up-Regulated Gα i3 Partially Compensates for the Missing Gα i2 . Deletion of one Gα i isoform in mice can provoke an up-regulation of the expression levels of the remaining isoforms, which may substitute for some but not all functions (17,19,(29)(30)(31)(32)(33)). Because we observed a clear-cut phenotype in the Gα i2 KO mice, we analyzed the expression of Gα i isoforms in their platelets.…”

Starch synthase IIIa and starch branching enzyme IIb-deficient mutant rice line ameliorates pancreatic insulin secretion in rats: screening and evaluating mutant rice lines with antidiabetic functionalities

“…To clarify the mechanism, further studies are needed. Although ornithine is known to promote insulin-like growth factor (47) , Leiss et al (48) recently reported that ornithine can also stimulate insulin secretion via Gα i2 , belonging to the G-protein family. Taken together, we consider that ornithine increased by #4019 ingestion contribute to the promotion of insulin secretion from the pancreas.…”