Proteasomal activation mediates down-regulation of inositol 1,4,5-trisphosphate receptor and calcium mobilization in rat pancreatic islets

Endocrinology
B LeeS G Laychock

Abstract

Inositol 1,4,5-trisphosphate receptor (IP3R) protein levels in isolated rat pancreatic islets were investigated in response to carbachol (CCh) and sulfated cholecystokinin 26-33 amide stimulation. Within 2 h, CCh reduced IP3R-I protein levels by 22% and IP3R-II and -III levels to 65% or more below basal. Sulfated cholecystokinin 26-33 amide decreased the levels of IP3R-I, -II, and -III by 34%, 60%, and 66% below basal, respectively. The effect of CCh was concentration- and time-dependent, with a persistent decline in IP3R levels for up to 6 h after the onset of stimulation. CCh-pretreated islets also showed an inhibition of glucose-stimulated insulin secretion. Proteasome inhibition completely blocked the down-regulatory effects of CCh on IP3Rs and significantly increased the insulin secretory response to glucose stimulation in the presence of CCH: Islet stimulation by glucose, alpha-ketoisocaproic acid, and tolbutamide completely protected IP3Rs against the down-regulatory effects of CCH: 2-deoxyglucose and 3-O-methyl glucose failed to affect CCh-induced IP3R down-regulation. The protective effects of glucose on IP3R down-regulation were completely inhibited by the Ca(2+) channel-blocking agent nimodipine. Intracellular Ca(2+)...Continue Reading

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Citations

Mar 9, 2005·Biochemical and Biophysical Research Communications·Zuheng MaAnneli Björklund
Jan 16, 2004·Trends in Pharmacological Sciences·Richard J H Wojcikiewicz
Dec 1, 2005·The Journal of Biological Chemistry·Cunnigaiper D BhanumathySuresh K Joseph
Apr 23, 2004·The Journal of Biological Chemistry·Sic L ChanMark P Mattson
Aug 28, 2009·Cell Calcium·Richard J H WojcikiewiczYuan Wang

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