COINCIDENCE OF EARLY GLUCOSE-INDUCED DEPOLARIZATION WITH LOWERING OF CYTOPLASMIC CA2(+) IN MOUSE PANCREATIC BETA-CELLS

1. The temporal relationship between the early glucose-induced changes of membrane potential and cytoplasmic Ca2+ concentration ([Ca2+](i)) was studied in insulin-releasing pancreatic beta-cells. 2. The mean resting membrane potential and [Ca2+](i) were about -70 mV and 60 nM, respectively, in 3 mM glucose. 3. Elevating the glucose concentration to 8-23 mM typically elicited a slow depolarization, which was paralleled by a lowering of [Ca2+](i). When the slow depolarization had reached a threshold of -55 to -40 mV, there was rapid further depolarization to a plateau with superimposed action potentials, and [Ca2+](i) increased dramatically. 4. Imposing hyperpolarizations and depolarizations of 1.0 mV from a holding potential of -70 mV had no detectable effect on [Ca2+](i). Furthermore, glucose elevation elicited a decrease in [Ca2+](i) even at a holding potential of -70 mV. 5. Step depolarizations induced [Ca2+](i) transients, which decayed with time courses well fitted by double exponentials. The slower component became faster by a factor of about 4 upon elevation of glucose, suggesting involvement of ATP-dependent Ca2+ sequestration or extrusion of [Ca2+](i). 6. Glucose stimulation increased the size and accelerated the recovery of carbachol-triggered [Ca2+](i) transients, and thapsigargin, an intracellular Ca2+-ATPase inhibitor, counteracted the glucose-induced lowering of [Ca2+](i), indicating that calcium transport into intracellular stores is involved in glucose-induced lowering of [Ca2+](i). 7. The results support the notion that in beta-cells, nutrient-induced elevation of ATP leads initially to ATP-dependent removal of Ca2+ from the cytoplasm, paralleled by a slow depolarization due to inhibition of ATP-sensitive K+ channels. Only after depolarization has reached a threshold do action potentials occur, inducing a sharp elevation in [Ca2+](i).