Inositol trisphosphate-dependent periodic activation of a Ca²⁺-activated K⁺ conductance in glucose-stimulated pancreatic β-cells

Abstract

GLUCOSE-STIMULATED insulin secretion is associated with the appearance of electrical activity in the pancreatic β-cell. At intermediate glucose concentrations, β-cell electrical activity follows a characteristic pattern of slow oscillations in membrane potential on which bursts of action potentials are superimposed¹. The electro-physiological background of the bursting pattern remains unestablished. Activation of Ca²⁺-activated large-conductance K⁺ channels (K_Ca channel²) has been implicated in this process³ but seems unlikely in view of recent evidence demonstrating that the β-cell electrical activity is unaffected by the specific K_Ca channel blocker charybdotoxin⁴. Another hypothesis postulates that the bursting arises as a consequence of two components of Ca²⁺-current inactivation⁵. Here we show that activation of a novel Ca²⁺-dependent K⁺ current in glucose-stimulated β-cells produces a transient membrane repolarization. This interrupts action potential firing so that action potentials appear in bursts. Spontaneous activity of this current was seen only rarely but could be induced by addition of compounds functionally related to hormones and neurotransmitters present in the intact pancreatic islet. K⁺ currents of the same type could be evoked by intracellular application of GTP, the effect of which was mediated by mobilization of Ca²⁺ from inositol 1,4,5-trisphosphate (InsP₃)-sensitive intracellular Ca²⁺ stores. These observations suggest that oscillatory glucose-stimulated electrical activity, which is correlated with pulsatile release of insulin⁶, results from the interaction between the β-cell and intraislet hormones and neurotransmitters. Our data also provide evidence for a close interplay between ion channels in theplasma membrane and InsP₃-induced mobilization of intracellular Ca²⁺ in an excitable cell.