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

Abstract

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 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 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 β-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 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 [Ca²⁺]_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.