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 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.
Kinard
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TA
Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0524, USA.
Satin
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D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid / Q000494:pharmacology; D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D048429:Cell Size / Q000502:physiology*; D018118:Chloride Channels / Q000187:drug effects / Q000502:physiology*; D000242:Cyclic AMP / Q000494:pharmacology*; D004553:Electric Conductivity; D005905:Glyburide / Q000494:pharmacology*; D007038:Hypotonic Solutions; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D051379:Mice
D018118:Chloride Channels; D007038:Hypotonic Solutions; D007328:Insulin; D015124:8-Bromo Cyclic Adenosine Monophosphate; D000255:Adenosine Triphosphate; D000242:Cyclic AMP; D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid; D005905:Glyburide