title: Alkali pH directly activates ATP-sensitive K+ channels and inhibits insulin secretion in beta-cells.
abstract: Glucose stimulation of pancreatic beta-cells is reported to lead to sustained alkalization, while extracellular application of weak bases is reported to inhibit electrical activity and decrease insulin secretion. We hypothesize that beta-cell K(ATP) channel activity is modulated by alkaline pH. Using the excised patch-clamp technique, we demonstrate a direct stimulatory action of alkali pH on recombinant SUR1/Kir6.2 channels due to increased open probability. Bath application of alkali pH similarly activates native islet beta-cell K(ATP) channels, leading to an inhibition of action potentials, and hyperpolarization of membrane potential. In situ pancreatic perfusion confirms that these cellular effects of alkali pH are observable at a functional level, resulting in decreases in both phase 1 and phase 2 glucose-stimulated insulin secretion. Our data are the first to report a stimulatory effect of a range of alkali pH on K(ATP) channel activity and link this to downstream effects on islet beta-cell function.
authors.affiliation: Department of Physiology, 3352 Medical Sciences Building, 1 King's College Circle, University of Toronto, Toronto, Ont., Canada. j.manningfox@utoronto.ca
authors.forename: Jocelyn E
authors.initials: JE
authors.lastname: Manning Fox
authors.forename: Gunce
authors.initials: G
authors.lastname: Karaman
authors.forename: Michael B
authors.initials: MB
authors.lastname: Wheeler
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000468:Alkalies / Q000737:chemistry; D000818:Animals; D006863:Hydrogen-Ion Concentration; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000502:physiology*; D008297:Male; D008564:Membrane Potentials; D051379:Mice; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D011955:Receptors, Drug / Q000378:metabolism*; D064233:Sulfonylurea Receptors; D000099161:Kcnj11 Channel
chemical_list: D018528:ATP-Binding Cassette Transporters; D000255:Adenosine Triphosphate; D000468:Alkalies; D007328:Insulin; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D000099161:Kcnj11 Channel; C577508:Abcc8 protein, mouse; C577509:Abcc8 protein, rat