title: Block of Kv1.7 potassium currents increases glucose-stimulated insulin secretion.
abstract: Glucose-stimulated insulin secretion (GSIS) relies on repetitive, electrical spiking activity of the beta cell membrane. Cyclic activation of voltage-gated potassium channels (K(v) ) generates an outward, 'delayed rectifier' potassium current, which drives the repolarizing phase of each spike and modulates insulin release. Although several K(v)  channels are expressed in pancreatic islets, their individual contributions to GSIS remain incompletely understood. We take advantage of a naturally occurring cone-snail peptide toxin, Conkunitzin-S1 (Conk-S1), which selectively blocks K(v) 1.7 channels to provide an intrinsically limited, finely graded control of total beta cell delayed rectifier current and hence of GSIS. Conk-S1 increases GSIS in isolated rat islets, likely by reducing K(v) 1.7-mediated delayed rectifier currents in beta cells, which yields increases in action potential firing and cytoplasmic free calcium. In rats, Conk-S1 increases glucose-dependent insulin secretion without decreasing basal glucose. Thus, we conclude that K(v) 1.7 contributes to the membrane-repolarizing current of beta cells during GSIS and that block of this specific component of beta cell K(v)  current offers a potential strategy for enhancing GSIS with minimal risk of hypoglycaemia during metabolic disorders such as Type 2 diabetes.
authors.affiliation: Department of Physiology and Pharmacology, and HBI, University of Calgary, Calgary, AB, Canada.
authors.forename: Rocio K
authors.initials: RK
authors.lastname: Finol-Urdaneta
authors.forename: Maria S
authors.initials: MS
authors.lastname: Remedi
authors.forename: Walter
authors.initials: W
authors.lastname: Raasch
authors.forename: Stefan
authors.initials: S
authors.lastname: Becker
authors.forename: Robert B
authors.initials: RB
authors.lastname: Clark
authors.forename: Nina
authors.initials: N
authors.lastname: Strüver
authors.forename: Evgeny
authors.initials: E
authors.lastname: Pavlov
authors.forename: Colin G
authors.initials: CG
authors.lastname: Nichols
authors.forename: Robert J
authors.initials: RJ
authors.lastname: French
authors.forename: Heinrich
authors.initials: H
authors.lastname: Terlau
mesh_terms: D000818:Animals; D012634:Bodily Secretions; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D008297:Male; D008978:Mollusk Venoms / Q000633:toxicity; D011188:Potassium / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D051637:Shaker Superfamily of Potassium Channels / Q000037:antagonists & inhibitors*
chemical_list: D007328:Insulin; C431140:KCNA7 protein, human; D008978:Mollusk Venoms; D051637:Shaker Superfamily of Potassium Channels; C504068:conkunitzin-S1, Conus striatus; D005947:Glucose; D011188:Potassium