Insulin Secretion and Ca2+ Dynamics in β-Cells Are Regulated by PERK (EIF2AK3) in Concert with Calcineurin

Protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) (EIF2AK3) is essential for normal development and function of the insulin-secreting -cell. Although genetic ablation of PERK in -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 -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 -cell Ca2+ signaling and insulin secretion, and that loss of this interaction may have profound implications in insulin secretion defects associated with diabetes.