AN ATP-SENSITIVE CL- CHANNEL CURRENT THAT IS ACTIVATED BY CELL SWELLING, CAMP, AND GLYBURIDE IN INSULIN-SECRETING CELLS

Although chloride ions are known to modulate insulin release and islet electrical activity, the mechanism or mechanisms mediating these effects are unclear. However, numerous studies of islet Cl- fluxes have suggested that Cl- movements are glucose and sulfonylurea sensitive and are blocked by stilbene-derivative Cl- channel blockers. We now show for the first time that insulin-secreting cells have a Cl- channel current, which we term I-Cl,I-islet. The current is activated by hypotonic conditions, 1-10 mu mol/l glyburide and 0.5 mmol/l 8-bromoadenosine 3':5'-cyclic monophosphate sodium, I-Cl,I-islet is mediated by Cl- channels, since replacing [Cl-](0) with less permeant aspartate reduces current amplitude and depolarizes its reversal potential, In addition, 100 mu mol/l 4,4'-diisothio-cyanatostilbene-2,2'-disulfonic acid (DIDS) or glyburide, which blocks the Cl- channels of other cell types, block I-Cl,I-islet. Reducing [ATP], reduces the amplitude of the current, suggesting that it may be under metabolic control, The current is time-independent and shows strong outward-rectification beyond similar to 0 mV, At potentials associated with the silent phase of islet electrical activity (approximately -65 mV), I-Cl,I-islet mediates a large inward current, which would be expected to depolarize islet membrane potential, Thus, activation of this novel current by increased intracellular cAMP, sulfonylureas, or ATP may contribute to the well-known depolarizing effects of these agents.