Document Detail

Glutaredoxin-1 mediates NADPH-dependent stimulation of calcium-dependent insulin secretion.
MedLine Citation:
PMID:  19299446     Owner:  NLM     Status:  MEDLINE    
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.
Thomas M Reinbothe; Rosita Ivarsson; Dai-Qing Li; Omid Niazi; Xingjun Jing; Enming Zhang; Lena Stenson; Ulrika Bryborn; Erik Renström
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-03-19
Journal Detail:
Title:  Molecular endocrinology (Baltimore, Md.)     Volume:  23     ISSN:  1944-9917     ISO Abbreviation:  Mol. Endocrinol.     Publication Date:  2009 Jun 
Date Detail:
Created Date:  2009-05-27     Completed Date:  2009-08-11     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8801431     Medline TA:  Mol Endocrinol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  893-900     Citation Subset:  IM    
Department of Clinical Sciences, Islet Pathophysiology, Lund University, Clinical Research Centre, Malmö, Sweden.
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MeSH Terms
Calcium / metabolism*
Cell Survival / drug effects
Exocytosis / drug effects
Gene Knockdown Techniques
Gene Silencing / drug effects
Glucose / pharmacology
Glutaredoxins / metabolism*
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
Subcellular Fractions / drug effects,  enzymology
Thioredoxins / metabolism
Reg. No./Substance:
0/Glrx1 protein, rat; 0/Glutaredoxins; 11061-68-0/Insulin; 50-99-7/Glucose; 52500-60-4/Thioredoxins; 53-59-8/NADP; 7440-70-2/Calcium

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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