Protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) (EIF2AK3) is essential for normal development and function of the insulin-secreting β-cell. Although genetic ablation of PERK in β-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 β-cells causes a rapid inhibition of secretagogue-stimulated subcellular Ca2+ signaling and insulin secretion. These dysfunctions stem from alterations in storeoperated Ca2+ 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 β-cell Ca2+ signaling and insulin secretion, and that loss of this interaction may have profound implications in insulin secretion defects associated with diabetes.
All Science Journal Classification (ASJC) codes
- Molecular Biology
- Cell Biology