Store‐operated Ca2+ entry mechanism is involved in glucose‐induced Ca2+ responses and insulin secretion, and is critical for preventing ER stress in primary pancreatic β‐cells.

Abstract

The role of the store‐operated channels and Ca2+ entry mechanism in β‐cell function is poorly understood. Using mouse pancreatic islets and dissociated primary β‐cells, we tested the hypothesis that inhibition of this mechanism may lead to ER stress, and impairment of glucose‐induced Ca2+ influx and insulin secretion. We found that store‐operated cation channels (cat‐SOC) are constitutively active in primary β‐cells. Inhibition of cat‐SOC with 2‐APB or DES caused significant reduction in high glucose‐induced Ca2+ responses in individual β‐cells, and nearly total oblation of insulin secretion by intact pancreatic islets. These effects were similar to that produced by inhibitors of voltage‐gated L type Ca2+ channels. We also found that sustained inhibition of cat‐SOC caused significant ER stress and CHOP expression in intact pancreatic islets. Moreover, functional inhibition of Ca2+‐ independent phospholipase A2β (PLA2g6) mimicked the effects of inhibition of cat‐SOC on glucose‐induced Ca2+ responses, insulin secretion and ER stress. Thus, PLA2g6 and cat‐SOC are critical for major β‐cell functions, and may be used as new therapeutic targets for preservation, or restoration of a normal pancreatic function.