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Glutaredoxin-1 mediates NADPH-dependent stimulation of calcium-dependent insulin secretion

Författare och institution:
Thomas Reinbothe (Institutionen för neurovetenskap och fysiologi, sektionen för fysiologi); R. Ivarsson (-); D. Q. Li (-); O. Niazi (-); X. Jing (-); E. Zhang (-); L. Stenson (-); U. Bryborn (-); E. Renstrom (-)
Publicerad i:
Mol Endocrinol, 23 ( 6 ) s. 893-900
1944-9917 (Electronic)
Artikel, refereegranskad vetenskaplig
Sammanfattning (abstract):
Nicotinamide adenine dinucleotide phosphate (NADPH) enhances Ca(2+)-induced exocytosis in pancreatic beta-cells, an effect suggested to involve the cytosolic redox protein glutaredoxin-1 (GRX-1). We here detail the role of GRX-1 in NADPH-stimulated beta-cell exocytosis and glucose-stimulated insulin secretion. Silencing of GRX-1 by RNA interference reduced glucose-stimulated insulin secretion in both clonal INS-1 832/13 cells and primary rat islets. GRX-1 silencing did not affect cell viability or the intracellular redox environment, suggesting that GRX-1 regulates the exocytotic machinery by a local action. By contrast, knockdown of the related protein thioredoxin-1 (TRX-1) was ineffective. Confocal immunocytochemistry revealed that GRX-1 locates to the cell periphery, whereas TRX-1 expression is uniform. These data suggest that the distinct subcellular localizations of TRX-1 and GRX-1 result in differences in substrate specificities and actions on insulin secretion. Single-cell exocytosis was likewise suppressed by GRX-1 knockdown in both rat beta-cells and clonal 832/13 cells, whereas after overexpression exocytosis increased by approximately 40%. Intracellular addition of NADPH (0.1 mm) stimulated Ca(2+)-evoked exocytosis in both cell types. Interestingly, the stimulatory action of NADPH on the exocytotic machinery coincided with an approximately 30% inhibition in whole-cell Ca(2+) currents. After GRX-1 silencing, NADPH failed to amplify insulin release but still inhibited Ca(2+) currents in 832/13 cells. In conclusion, NADPH stimulates the exocytotic machinery in pancreatic beta-cells. This effect is mediated by the NADPH acceptor protein GRX-1 by a local redox reaction that accelerates beta-cell exocytosis and, in turn, insulin secretion.
Ämne (baseras på Högskoleverkets indelning av forskningsämnen):
Medicinska grundvetenskaper ->
Cell- och molekylärbiologi
Medicinska grundvetenskaper ->
Cell- och molekylärbiologi ->
Patologi ->
Molekylär medicin
Animals, Calcium/*metabolism, Cell Survival/drug effects, Exocytosis/drug effects, Gene Knockdown Techniques, Gene Silencing/drug effects, Glucose/pharmacology, Glutaredoxins/*metabolism, Immunohistochemistry, Insulin/*secretion, Insulin-Secreting Cells/cytology/drug effects/enzymology/secretion, Intracellular Space/drug effects/enzymology, NADP/*metabolism, Oxidation-Reduction/drug effects, Protein Transport/drug effects, Rats, Subcellular Fractions/drug effects/enzymology, Thioredoxins/metabolism
Postens nummer:
Posten skapad:
2016-08-09 11:08

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