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

OBJECTIVE-Ca2+-regulated K+ channels are involved in numerous Ca2+-dependent signaling pathways. In this study, we investigated whether the Ca2+-activated K+ channel of intermediate conductance SK4 (KCa3.1, IK1) plays a physiological role in pancreatic beta-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 Ca2+ concentration ([Ca2+](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 Ca2+ action potential frequency, and single-action potentials were broadened. These alterations were coupled to increased [Ca2+](c). In addition, glucose responsiveness of membrane potential, [Ca2+](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 mu mol/l). Accordingly, the SK4 channel blocker TRAM-34 (1 mu mol/l) partly inhibited K-Ca currents and induced electrical activity at a threshold glucose concentration. In stimulated WT beta-cells, TRAM-34 further increased [Ca2+](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. Diabetes 58:1835-1843, 2009