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 effe cts are unclear. However, numerous studies of islet Cl- fluxes have su ggested that Cl- movements are glucose and sulfonylurea sensitive and are blocked by stilbene-derivative Cl- channel blockers. We now show f or the first time that insulin-secreting cells have a Cl- channel curr ent, 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- chan nels, since replacing [Cl-](0) with less permeant aspartate reduces cu rrent amplitude and depolarizes its reversal potential, In addition, 1 00 mu mol/l 4,4'-diisothio-cyanatostilbene-2,2'-disulfonic acid (DIDS) or glyburide, which blocks the Cl- channels of other cell types, bloc k 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 electric al activity (approximately -65 mV), I-Cl,I-islet mediates a large inwa rd current, which would be expected to depolarize islet membrane poten tial, Thus, activation of this novel current by increased intracellula r cAMP, sulfonylureas, or ATP may contribute to the well-known depolar izing effects of these agents.