P. B. Goforth, R. Bertram, F. A. Khan, M. Zhang, A. Sherman, L. S. Satin

A novel calcium-dependent potassium current (Kslow) that slowly activates in response to a simulated islet burst was identified recently in mouse pancreatic beta-cells. Kslow activation may help terminate the cyclic bursts of calcium-dependent action potentials that drive calcium influx and insulin secretion in beta-cells. Here, we report that when calcium handling was disrupted by blocking calcium uptake into the ER with two separate agents reported to block the sarco/endoplasmic calcium ATPase (SERCA), thapsigargin (1-5 uM) or insulin (200 nM), Kslow was transiently potentiated and then inhibited. Kslow amplitude could also be inhibited by increasing extracellular glucose concentration from 5 to 10 mM. The biphasic modulation of Kslow by SERCA blockers could not be explained by a minimal mathematical model in which calcium is divided between two compartments, the cytosol and the ER, and Kslow activation mirrors changes in cytosolic calcium induced by the burst protocol. However, the experimental findings were reproduced by a model in which Kslow activation is mediated by a localized pool of calcium in a subspace located between the ER and the plasma membrane. In this model, the subspace calcium follows changes in cytosolic calcium but with a gradient that reflects calcium efflux from the ER. Slow modulation of this gradient as the ER empties and fills may enhance the role of Kslow and calcium handling in influencing beta-cell electrical activity and insulin secretion.