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, themechanism or mechanisms mediating these effects are unclear. However, numerous studies of islet Cl⁻ fluxes have suggested that Cl⁻ movements and 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,islet· The current is activated by hypotonic conditions, 1–10 μmol/l glyburide and 0.5 mmol/l 8-bromoadenosine 3′:5′-cyclic monophosphate sodium. I_Cl,islet is mediated by Cl⁻ channels, since replacing [Cl⁻]_o with less permeant aspartate reduces current amplitude and depolarizes its reversal potential. In addition, 100 μmol/l 4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid (DIDS) or glyburide, which blocks the Cl⁻ channels of other cell types, block I_Cl,islet· Reducing [ATP]_i reduces the amplitude of the current, suggesting thatit may be under metabolic control. The current is time-independent and shows strong outward-rectification beyond ∼0 mV. At potentials associated with the silent phase of islet electrical activity (approximately −65 mV), I_Cl,islet mediates a large inward current, which would be expected to depolarize islet membrane potential. Thus, activation of this novel current byincreased intracellular cAMP, sulfonylureas, or ATP may contribute to the well-known depolarizing effects of these agents.