Enhanced glucose tolerance by SK4 channel inhibition in pancreatic beta-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 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 Ca(2+) concentration (Ca(2+)) 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+). In addition, glucose responsiveness of membrane potential, Ca(2+), 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+) 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.