Glucose-induced mixed [Ca ]c oscillations in mouse -cells are controlled by the membrane potential and the SERCA3 Ca -ATPase of the endoplasmic reticulum

Beauvois, Melanie C., Charafa Merezak, Jean-Christophe Jonas, Magalie A. Ravier, Jean-Claude Henquin, and Patrick Gilon. Glucose-induced mixed [Ca ]c oscillations in mouse -cells are controlled by the membrane potential and SERCA3 Ca -ATPase of the endoplasmic reticulum. Am J Physiol Cell Physiol 290: C1503–C1511, 2006. First published December 28, 2005; doi:10.1152/ajpcell.00400.2005.—Stimulatory concentrations of glucose induce two patterns of cytosolic Ca concentration ([Ca ]c) oscillations in mouse islets: simple or mixed. In the mixed pattern, rapid oscillations are superimposed on slow ones. In the present study, we examined the role of the membrane potential in the mixed pattern and the impact of this pattern on insulin release. Simultaneous measurement of [Ca ]c and insulin release from single islets revealed that mixed [Ca ]c oscillations triggered synchronous oscillations of insulin secretion. Simultaneous recordings of membrane potential in a single -cell within an islet and of [Ca ]c in the whole islet demonstrated that the mixed pattern resulted from compound bursting (i.e., clusters of membrane potential oscillations separated by prolonged silent intervals) that was synchronized in most -cells of the islet. Each slow [Ca ]c increase during mixed oscillations was due to a progressive summation of rapid oscillations. Digital image analysis confirmed the good synchrony between subregions of an islet. By contrast, islets from sarco(endo)plasmic reticulum Ca -ATPase isoform 3 (SERCA3)-knockout mice did not display typical mixed [Ca ]c oscillations in response to glucose. This results from a lack of progressive summation of rapid oscillations and from altered spontaneous electrical activity, i.e., lack of compound bursting, and membrane potential oscillations characterized by lowerfrequency but larger-depolarization phases than observed in SERCA3 / -cells. We conclude that glucose-induced mixed [Ca ]c oscillations result from compound bursting in all -cells of the islet. Disruption of SERCA3 abolishes mixed [Ca ]c oscillations and augments -cell depolarization. This latter observation indicates that the endoplasmic reticulum participates in the control of the -cell membrane potential during glucose stimulation.