ENDOPLASMIC-RETICULUM CALCIUM STORE REGULATES MEMBRANE-POTENTIAL IN MOUSE ISLET BETA-CELLS

Glucose stimulation of islet beta-cell insulin secretion is initiated by membrane depolarization and an elevation in intracellular free calc ium concentration ([Ca2+](i)) from a combination of influx through dep olarization-activated Ca2+ channels and intracellular Ca2+ store relea se. Prevention of Ca2+ store refilling with thapsigargin produced a su stained depolarization, leading to enhanced Ca2+ influx and an elevati on in [Ca2+](i) in 12 mM glucose. Depletion of intracellular Ca2+ stor es by external EGTA reduced [Ca2+](i) and also caused a long lasting d epolarization. In single beta-cells, external EGTA activated an inward current, the voltage range and kinetic properties of which differed f rom those of voltage-dependent Ca2+ channels. A novel pathway thus exi sts in beta-cells by which depletion of endoplasmic reticulum Ca2+ sto res results in the activation of an inward current that, by inducing d epolarization, facilitates Ca2+ influx through voltage-gated Ca2+ chan nels. The physiological relevance of this pathway in the control of be ta cell function is indicated by the stimulation of insulin secretion by thapsigargin.