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

T. A. Kinard, L. S. Satin
1995 Diabetes  
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 insulinsecreting cells have a Cl~ channel current, which we term Ici,isiet* 10 , current is activated by hypotonic conditions,
more » ... 1-10 fxmol/1 glyburide and 0.5 mmol/1 8-bromoadenosine 3':5'-cyclic monophosphate sodium. I C i )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 fxmol/1 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS) or glyburide, which blocks the Cl~ channels of other cell types, block I c l i s l e t . Reducing [ATPJj 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 ~0 mV. At potentials associated with the silent phase of islet electrical activity (approximately -6 5 mV), I C i,isiet 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. Diabetes 44:1461-1466, 1995 C hloride ion channels exist in virtually all mammalian cells (1,2) but have never been reported in insulin-secreting cells. It has been known for some time, however, that Cl" is important for islet function, since replacement of [Cl~] o with other anions or the addition of anion transport blockers alters glucosedependent insulin secretion (3-6) and islet electrical activity (7,8). In addition, numerous studies of 36 C1 fluxes have shown that islets have a substantial permeability to ClF
doi:10.2337/diab.44.12.1461 pmid:7589855 fatcat:5xi5kbcii5fijmzektabjigdcy