详细记录  
题名:Insulin Secretion and Ca2+ Dynamics in beta-Cells Are Regulated by PERK (EIF2AK3) in Concert with Calcineurin.
作者:WANG R; MCGRATH BC; KOPP RF; ROE MW; TANG X; CHEN G; CAVENER DR;
来源:J Biol Chem. 2013 Nov 22;288(47):33824-36. doi: 10.1074/jbc.M113.503664. Epub [ IF= 0.00 ] ]
URL :10.1074/jbc.M113.503664
日期:20131203
摘要:Protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) (EIF2AK3) is
essential for normal development and function of the insulin-secreting beta-cell.
Although genetic ablation of PERK in beta-cells results in permanent neonatal
diabetes in humans and mice, the underlying mechanisms remain unclear. Here, we
used a newly developed and highly specific inhibitor of PERK to determine the
immediate effects of acute ablation of PERK activity. We found that inhibition of
PERK in human and rodent beta-cells causes a rapid inhibition of
secretagogue-stimulated subcellular Ca(2+) signaling and insulin secretion. These
dysfunctions stem from alterations in store-operated Ca(2+) entry and
sarcoplasmic endoplasmic reticulum Ca(2+)-ATPase activity. We also found that
PERK regulates calcineurin, and pharmacological inhibition of calcineurin results
in similar defects on stimulus-secretion coupling. Our findings suggest that
interplay between calcineurin and PERK regulates beta-cell Ca(2+) signaling and
insulin secretion, and that loss of this interaction may have profound
implications in insulin secretion defects associated with diabetes.

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