title: Enhanced glucose tolerance by SK4 channel inhibition in pancreatic beta-cells.
abstract: OBJECTIVE
  Ca(2+)-regulated K(+) channels are involved in numerous Ca(2+)-dependent signaling pathways. In this study, we investigated whether the Ca(2+)-activated K(+) channel of intermediate conductance SK4 (KCa3.1, IK1) plays a physiological role in pancreatic beta-cell function.
  
  
  METHODS
  Glucose tolerance and insulin sensitivity were determined in wild-type (WT) or SK4 knockout (SK4-KO) mice. Electrophysiological experiments were performed with the patch-clamp technique. The cytosolic Ca(2+) concentration ([Ca(2+)](c)) was determined by fura-2 fluorescence. Insulin release was assessed by radioimmunoassay, and SK4 protein was detected by Western blot analysis.
  
  
  RESULTS
  SK4-KO mice showed improved glucose tolerance, whereas insulin sensitivity was not altered. The animals were not hypoglycemic. Isolated SK4-KO beta-cells stimulated with 15 mmol/l glucose had an increased Ca(2+) action potential frequency, and single-action potentials were broadened. These alterations were coupled to increased [Ca(2+)](c). In addition, glucose responsiveness of membrane potential, [Ca(2+)](c), and insulin secretion were shifted to lower glucose concentrations. SK4 protein was expressed in WT islets. An increase in K(+) currents and concomitant membrane hyperpolarization could be evoked in WT beta-cells by the SK4 channel opener DCEBIO (100 micromol/l). Accordingly, the SK4 channel blocker TRAM-34 (1 micromol/l) partly inhibited K(Ca) currents and induced electrical activity at a threshold glucose concentration. In stimulated WT beta-cells, TRAM-34 further increased [Ca(2+)](c) and broadened action potentials similar to those seen in SK4-KO beta-cells. SK4 channels were found to substantially contribute to K(slow) (slowly activating K(+) current).
  
  
  CONCLUSIONS
  SK4 channels are involved in beta-cell stimulus-secretion coupling. Deficiency of SK4 current induces elevated beta-cell responsiveness and coincides with improved glucose tolerance in vivo. Therefore, pharmacologic modulation of these channels might provide an interesting approach for the development of novel insulinotropic drugs.
authors.affiliation: Institute of Pharmacy, the Department of Pharmacology, University of Tübingen, Tübingen, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Düfer
authors.forename: Belinda
authors.initials: B
authors.lastname: Gier
authors.forename: Daniela
authors.initials: D
authors.lastname: Wolpers
authors.forename: Peter
authors.initials: P
authors.lastname: Krippeit-Drews
authors.forename: Peter
authors.initials: P
authors.lastname: Ruth
authors.forename: Gisela
authors.initials: G
authors.lastname: Drews
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D003433:Crosses, Genetic; D005260:Female; D005951:Glucose Tolerance Test; D050417:Insulin-Secreting Cells / Q000502:physiology*; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000172:deficiency*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout
chemical_list: D001786:Blood Glucose; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496925:Kcnn4 protein, mouse