Referenced in: none

Automatically associated channels: ClC3 , ClC4

Title: Suppression of sulfonylurea- and glucose-induced insulin secretion in vitro and in vivo in mice lacking the chloride transport protein ClC-3.

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 Mörgelin, Lena Eliasson, Patrik Rorsman, Erik Renström

Journal, date & volume: Cell Metab., 2009 Oct , 10, 309-15

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/19808023

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 beta 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 approximately 80% reduction in depolarization-evoked beta cell exocytosis (monitored as increases in cell capacitance) in single ClC-3(-/-) beta 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.