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题名:Insulin secretion and Ca2+ dynamics in beta-cells are regulated by PERK eIF2alpha kinase 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 Oct 10. [ IF= 0.00 ] ]
URL :10.1074/jbc.M113.503664
日期:20131104
摘要: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 Ca2+ signaling and
insulin secretion. These dysfunctions stem from alterations in store-operated
Ca2+ entry and sarcoplasmic-endoplasmic reticulum Ca2+ 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
Ca2+ 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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