Calcium-activated K super(+) Channels of Mouse beta -cells are Controlled by Both Store and Cytoplasmic Ca super(2+): Experimental and Theoretical Studies

A novel calcium-dependent potassium current (K sub(slow)) that slowly activates in response to a simulated islet burst was identified recently in mouse pancreatic beta -cells (Goepel, S.O., T. Kanno, S. Barg, L. Eliasson, J. Galvanovskis, E. Renstroem, and P. Rorsman. 1999. J. Gen. Physiol. 114:759-769). K sub(slow) activation may help terminate the cyclic bursts of Ca super(2+)-dependent action potentials that drive Ca super(2+) influx and insulin secretion in beta -cells. Here, we report that when [Ca super(2+)] sub(i) handling was disrupted by blocking Ca super(2+) uptake into the ER with two separate agents reported to block the sarco/endoplasmic calcium ATPase (SERCA), thapsigargin (1-5 mu M) or insulin (200 nM), K sub(slow) was transiently potentiated and then inhibited. K sub(slow) amplitude could also be inhibited by increasing extracellular glucose concentration from 5 to 10 mM. The biphasic modulation of K sub(slow) by SERCA blockers could not be explained by a minimal mathematical model in which [Ca super(2+)] sub(i) is divided between two compartments, the cytosol and the ER, and K sub(slow) activation mirrors changes in cytosolic calcium induced by the burst protocol. However, the experimental findings were reproduced by a model in which K sub(slow) activation is mediated by a localized pool of [Ca super(2+)] in a subspace located between the ER and the plasma membrane. In this model, the subspace [Ca super(2+)] follows changes in cytosolic [Ca super(2+)] but with a gradient that reflects Ca super(2+) efflux from the ER. Slow modulation of this gradient as the ER empties and fills may enhance the role of K sub(slow) and [Ca super(2+)] handling in influencing beta -cell electrical activity and insulin secretion.