title: BK channels affect glucose homeostasis and cell viability of murine pancreatic beta cells.
abstract: OBJECTIVE
  Evidence is accumulating that Ca(2+)-regulated K(+) (K(Ca)) channels are important for beta cell function. We used BK channel knockout (BK-KO) mice to examine the role of these K(Ca) channels for glucose homeostasis, beta cell function and viability.
  
  
  METHODS
  Glucose and insulin tolerance were tested with male wild-type and BK-KO mice. BK channels were detected by single-cell RT-PCR, cytosolic Ca(2+) concentration ([Ca(2+)](c)) by fura-2 fluorescence, and insulin secretion by radioimmunoassay. Electrophysiology was performed with the patch-clamp technique. Apoptosis was detected via caspase 3 or TUNEL assay.
  
  
  RESULTS
  BK channels were expressed in murine pancreatic beta cells. BK-KO mice were normoglycaemic but displayed markedly impaired glucose tolerance. Genetic or pharmacological deletion of the BK channel reduced glucose-induced insulin secretion from isolated islets. BK-KO and BK channel inhibition (with iberiotoxin, 100 nmol/l) broadened action potentials and abolished the after-hyperpolarisation in glucose-stimulated beta cells. However, BK-KO did not affect action potential frequency, the plateau potential at which action potentials start or glucose-induced elevation of [Ca(2+)](c). BK-KO had no direct influence on exocytosis. Importantly, in BK-KO islet cells the fraction of apoptotic cells and the rate of cell death induced by oxidative stress (H(2)O(2), 10-100 μmol/l) were significantly increased compared with wild-type controls. Similar effects were obtained with iberiotoxin. Determination of H(2)O(2)-induced K(+) currents revealed that BK channels contribute to the hyperpolarising K(+) current activated under conditions of oxidative stress.
  
  
  CONCLUSIONS
  Ablation or inhibition of BK channels impairs glucose homeostasis and insulin secretion by interfering with beta cell stimulus-secretion coupling. In addition, BK channels are part of a defence mechanism against apoptosis and oxidative stress.
authors.affiliation: Department of Pharmacology and Toxicology, Institute of Pharmacy, University of Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Düfer
authors.forename: Y
authors.initials: Y
authors.lastname: Neye
authors.forename: K
authors.initials: K
authors.lastname: Hörth
authors.forename: P
authors.initials: P
authors.lastname: Krippeit-Drews
authors.forename: A
authors.initials: A
authors.lastname: Hennige
authors.forename: H
authors.initials: H
authors.lastname: Widmer
authors.forename: H
authors.initials: H
authors.lastname: McClafferty
authors.forename: M J
authors.initials: MJ
authors.lastname: Shipston
authors.forename: H-U
authors.initials: HU
authors.lastname: Häring
authors.forename: P
authors.initials: P
authors.lastname: Ruth
authors.forename: G
authors.initials: G
authors.lastname: Drews
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D004594:Electrophysiology; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism*
chemical_list: D015221:Potassium Channels; D005947:Glucose