title: Control of voltage-gated potassium channel Kv2.2 expression by pyruvate-isocitrate cycling regulates glucose-stimulated insulin secretion.
abstract: Recent studies have shown that the pyruvate-isocitrate cycling pathway, involving the mitochondrial citrate/isocitrate carrier and the cytosolic NADP-dependent isocitrate dehydrogenase (ICDc), is involved in control of glucose-stimulated insulin secretion (GSIS). Here we demonstrate that pyruvate-isocitrate cycling regulates expression of the voltage-gated potassium channel family member Kv2.2 in islet β-cells. siRNA-mediated suppression of ICDc, citrate/isocitrate carrier, or Kv2.2 expression impaired GSIS, and the effect of ICDc knockdown was rescued by re-expression of Kv2.2. Moreover, chronic exposure of β-cells to elevated fatty acids, which impairs GSIS, resulted in decreased expression of Kv2.2. Surprisingly, knockdown of ICDc or Kv2.2 increased rather than decreased outward K(+) current in the 832/13 β-cell line. Immunoprecipitation studies demonstrated interaction of Kv2.1 and Kv2.2, and co-overexpression of the two channels reduced outward K(+) current compared with overexpression of Kv2.1 alone. Also, siRNA-mediated knockdown of ICDc enhanced the suppressive effect of the Kv2.1-selective inhibitor stromatoxin1 on K(+) currents. Our data support a model in which a key function of the pyruvate-isocitrate cycle is to maintain levels of Kv2.2 expression sufficient to allow it to serve as a negative regulator of Kv channel activity.
authors.affiliation: Duke Institute of Molecular Physiology, Duke University Medical Center, Durham, North Carolina 27704, USA.
authors.forename: Mette V
authors.initials: MV
authors.lastname: Jensen
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Haldeman
authors.forename: Hengtao
authors.initials: H
authors.lastname: Zhang
authors.forename: Danhong
authors.initials: D
authors.lastname: Lu
authors.forename: Mark O
authors.initials: MO
authors.lastname: Huising
authors.forename: Wylie W
authors.initials: WW
authors.lastname: Vale
authors.forename: Hans E
authors.initials: HE
authors.lastname: Hohmeier
authors.forename: Paul
authors.initials: P
authors.lastname: Rosenberg
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Newgard
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D005947:Glucose / Q000235:genetics / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology; D017136:Ion Transport / Q000187:drug effects / Q000502:physiology; D007521:Isocitrate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D007523:Isocitrates / Q000378:metabolism*; D008297:Male; D008954:Models, Biological; D010455:Peptides / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism; D019289:Pyruvic Acid / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D051669:Shab Potassium Channels / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D013111:Spider Venoms / Q000494:pharmacology
chemical_list: D007328:Insulin; D007523:Isocitrates; D010455:Peptides; D051669:Shab Potassium Channels; D013111:Spider Venoms; C560803:stromatoxin protein, Stromatopelma calceata; D019289:Pyruvic Acid; C034219:isocitric acid; D007521:Isocitrate Dehydrogenase; C039355:isocitrate dehydrogenase (NADP+); D005947:Glucose; D011188:Potassium
keywords: Diabetes; Glucose Metabolism; Insulin Secretion; Ion Channels; Pancreatic Islets