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 beta-cell. At intermediate glucose concentrations, beta-cell electrical activity follows a characteristic pattern of slow oscillations in membrane potential on which bursts of action potentials are superimposed. The electrophysiological background of the bursting pattern remains unestablished. Activation of Ca(2+)-activated large-conductance K+ channels (KCa channel) has been implicated in this process but seems unlikely in view of recent evidence demonstrating that the beta-cell electrical activity is unaffected by the specific KCa channel blocker charybdotoxin. Another hypothesis postulates that the bursting arises as a consequence of two components of Ca(2+)-current inactivation. Here we show that activation of a novel Ca(2+)-dependent K+ current in glucose-stimulated beta-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 insulin, results from the interaction between the beta-cell and intraislet hormones and neurotransmitters. Our data also provide evidence for a close interplay between ion channels in the plasma membrane and InsP3-induced mobilization of intracellular Ca2+ in an excitable cell.

Oscillations of membrane potential and cytosolic Ca2+ concentration in SUR1−/− beta cells

“…Our patch-clamp experiments could be interpreted to suggest that [Ca 2+ ] c oscillations in isolated SUR1 −/− beta cells are regulated independently of membrane potential. However, it is often difficult to detect membrane potential oscillations when patch-clamping single or small clusters of beta cells [27,28,29], although they invariably occur in experiments with intact islets [37], when electrically coupled cells, surrounded by nerve endings and blood vessels, are impaled by intracellular microelectrodes. In short, microelectrode impalements are a better reflection of the situation in vivo than patch-clamp experiments.…”

“…2e, n=6) 2+ ] c observed in cells with functional K ATP channels could be abrogated in SUR1 −/− beta cells. To test this point we measured the cell membrane potential in intact islets using intracellular microelectrodes since oscillatory activity is difficult to detect in single beta cells [27,28,29]. Surprisingly, the membrane potential of SUR1 −/− beta cells oscillated under these conditions in the presence of 15 mmol/l glucose (n=8, Fig.…”

Beta-cell hubs maintain Ca2+ oscillations in human and mouse islet simulations

“…29 A similar system has long been postulated to exist in the islet, whereby specialized β-cells generate and pace the Ca 2+ oscillations necessary for insulin secretion. 30-32 Recently, Johnston et al . 33 demonstrated, by using functional cell mapping and optogenetics, that certain β-cells (termed ‘hubs’) are indispensable for the maintenance of Ca 2+ activity in the islet.…”

Feedback Control of the ATP-Sensitive K+ Current by Cytosolic Ca2+ Contributes to Oscillations of the Membrane Potential in Pancreatic β-Cells

“…Several hypotheses have been put forward. They include activation of Ca 2ϩ -dependent K ϩ channels (11)(12)(13)(14) different from the charybdotoxin-sensitive K ϩ channel (15); slow inactivation of voltage-dependent Ca 2ϩ channels (3,16); decrease of cell-to-cell coupling (17) or of a storeoperated current (18,19); and increase of I KATP (20 -22 (23,24) or be driven by Ca 2ϩ in a sort of negative feedback control (20,21,(25)(26)(27).…”