Suppression of Sulfonylurea- and Glucose-Induced Insulin Secretion In Vitro and In Vivo in Mice Lacking the Chloride Transport Protein ClC-3 |
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Authors: | Dai-Qing Li Xingjun Jing Albert Salehi Stephan C Collins Michael B Hoppa Anders H Rosengren Enming Zhang Ingmar Lundquist Charlotta S Olofsson Matthias Mrgelin Lena Eliasson Patrik Rorsman Erik Renstrm |
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Institution: | 1Lund University Diabetes Center, Department of Clinical Sciences Malmö, Lund University, Malmö, SE-205 02 Malmö, Sweden;2Key Lab of Hormones and Development, Ministry of Health, China, Tianjin Metabolic Diseases Hospital, Tianjin Medical University, China;3Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford OX3 7LJ, UK;4Department of Physiology, Göteborg University, Medicinaregatan 11, Box 432, SE-405 30 Göteborg, Sweden;5Department of Clinical Sciences Lund, Division of Infection Medicine, Lund University, SE-221 84 Lund, Sweden |
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Abstract: | Priming of insulin secretory granules for release requires intragranular acidification and depends on vesicular Cl−-fluxes, but the identity of the chloride transporter/ion channel involved is unknown. We tested the hypothesis that the chloride transport protein ClC-3 fulfills these actions in pancreatic β cells. In ClC-3−/− mice, insulin secretion evoked by membrane depolarization (high extracellular K+, sulfonylureas), or glucose was >60% reduced compared to WT animals. This effect was mirrored by a 80% reduction in depolarization-evoked β cell exocytosis (monitored as increases in cell capacitance) in single ClC-3−/− β cells, as well as a 44% reduction in proton transport across the granule membrane. ClC-3 expression in the insulin granule was demonstrated by immunoblotting, immunostaining, and negative immuno-EM in a high-purification fraction of large dense-core vesicles (LDCVs) obtained by phogrin-EGFP labeling. The data establish the importance of granular Cl− fluxes in granule priming and provide direct evidence for the involvement of ClC-3 in the process. |
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Keywords: | CELLBIO HUMDISEASE |
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