An ATP-Sensitive Cl− Channel Current That Is Activated by Cell Swelling, cAMP, and Glyburide in Insulin-Secreting Cells

Abstract

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 ICl,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. ICl,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 ICl,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), ICl,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.