Enhanced Glucose Tolerance by SK4 Channel Inhibition in Pancreatic β-Cells

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 β-cell function. RESEARCH DESIGN AND 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 β-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 β-cells by the SK4 channel opener DCEBIO (100 μmol/l). Accordingly, the SK4 channel blocker TRAM-34 (1 μmol/l) partly inhibited K(Ca) currents and induced electrical activity at a threshold glucose concentration. In stimulated WT β-cells, TRAM-34 further increased [Ca(2+)](c) and broadened action potentials similar to those seen in SK4-KO β-cells. SK4 channels were found to substantially contribute to K(slow) (slowly activating K(+) current). CONCLUSIONS: SK4 channels are involved in β-cell stimulus-secretion coupling. Deficiency of SK4 current induces elevated β-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.