| Glutaredoxin-1 mediates NADPH-dependent stimulation of calcium-dependent insulin secretion. | |
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MedLine Citation:
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PMID: 19299446 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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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:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2009-03-19 |
Journal Detail:
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Title: Molecular endocrinology (Baltimore, Md.) Volume: 23 ISSN: 1944-9917 ISO Abbreviation: Mol. Endocrinol. Publication Date: 2009 Jun |
Date Detail:
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Created Date: 2009-05-27 Completed Date: 2009-08-11 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8801431 Medline TA: Mol Endocrinol Country: United States |
Other Details:
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Languages: eng Pagination: 893-900 Citation Subset: IM |
Affiliation:
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Department of Clinical Sciences, Islet Pathophysiology, Lund University, Clinical Research Centre, Malmö, Sweden. thomas.reinbothe@med.lu.se |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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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 |
| Chemical | |
Reg. No./Substance:
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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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