title: The granular chloride channel ClC-3 is permissive for insulin secretion.
abstract: Insulin secretion from pancreatic beta cells is dependent on maturation and acidification of the secretory granule, processes necessary for prohormone convertase cleavage of proinsulin. Previous studies in isolated beta cells revealed that acidification may be dependent on the granule membrane chloride channel ClC-3, in a step permissive for a regulated secretory response. In this study, immuno-EM of beta cells revealed colocalization of ClC-3 and insulin on secretory granules. Clcn3(-/-) mice as well as isolated islets demonstrate impaired insulin secretion; Clcn3(-/-) beta cells are defective in regulated insulin exocytosis and granular acidification. Increased amounts of proinsulin were found in the majority of secretory granules in the Clcn3(-/-) mice, while in Clcn3(+/+) cells, proinsulin was confined to the immature secretory granules. These results demonstrate that in pancreatic beta cells, chloride channels, specifically ClC-3, are localized on insulin granules and play a role in insulin processing as well as insulin secretion through regulation of granular acidification.
authors.affiliation: Department of Neurobiology, Pharmacology, and Physiology, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Ludmila V
authors.initials: LV
authors.lastname: Deriy
authors.forename: Erwin A
authors.initials: EA
authors.lastname: Gomez
authors.forename: David A
authors.initials: DA
authors.lastname: Jacobson
authors.forename: XueQing
authors.initials: X
authors.lastname: Wang
authors.forename: Jessika A
authors.initials: JA
authors.lastname: Hopson
authors.forename: Xiang Y
authors.initials: XY
authors.lastname: Liu
authors.forename: Guangping
authors.initials: G
authors.lastname: Zhang
authors.forename: Vytautas P
authors.initials: VP
authors.lastname: Bindokas
authors.forename: Louis H
authors.initials: LH
authors.lastname: Philipson
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Nelson
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002478:Cells, Cultured; D018118:Chloride Channels / Q000235:genetics / Q000378:metabolism*; D002712:Chlorides / Q000378:metabolism; D003594:Cytoplasmic Granules / Q000378:metabolism / Q000648:ultrastructure; D005089:Exocytosis / Q000502:physiology; D006863:Hydrogen-Ion Concentration; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011384:Proinsulin / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D018118:Chloride Channels; D002712:Chlorides; C115376:ClC-3 channel; D007328:Insulin; D011384:Proinsulin