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, the mechanism 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 mumol/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 mumol/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 that it may be under metabolic control. The current is time-independent and shows strong outward-rectification beyond approximately 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 by increased intracellular cAMP, sulfonylureas, or ATP may contribute to the well-known depolarizing effects of these agents.