MODEL OF BETA-CELL MITOCHONDRIAL CALCIUM HANDLING AND ELECTRICAL-ACTIVITY - I - CYTOPLASMIC VARIABLES

We continue our development of a kinetic model of bursting electrical activity in the pancreatic beta-cell (J. Keizer and G. Magnus. Biophys . J. 56: 229-242, 1989), including the influence of Ca2+ handling by t he mitochondria. Our minimal model of mitochondrial Ca2+ handling [G. Magnus and J. Keizer. Am. J. Physiol. 273 (Cell Physiol. 42): C717-C73 3, 1997] is expanded to include the D-glucose dependence of the rate o f production of mitochondrial reducing equivalents. The Ca2+ dependenc e of the mitochondrial dehydrogenases, which is also included in the m odel, plays only a small role in the simulations, since the dehydrogen ases appear to be maximally activated when D-glucose concentrations ar e sufficient to produce bursting. A previous model of ionic currents i n the plasma membrane is updated using a recent experimental character ization of the dependence of the conductance of the ATP-sensitive K+ ( K-ATP) current on adenine nucleotides. The resulting whole cell model is complex, involving 12 dynamic variables that couple Ca2+ handling i n the cytoplasm and the mitochondria with electrical activity in the p lasma and inner mitochondrial membranes. Simulations with the whole ce ll model give rise to bursting electrical activity similar to that see n in pancreatic islets and clusters of pancreatic beta-cells. The full D-glucose dose response of electrical activity is obtained if the cyt osolic rate of ATP hydrolysis is a sigmoidal function of glucose. The simulations give the correct shape, period, and phase of the associate d oscillations in cytosolic Ca2+, predict that the conductance of the K-ATP current oscillates out of phase with electrical activity [as rec ently observed in ob/ob mice (O. Larsson, H. Kindmark, R. Branstrom, B . Fredholm, and P.-O. Berggren. Proc. Natl. Acad. Sci. USA 93: 5161-51 65, 1996)], and make other novel predictions. In this model, bursting results because Ca2+ uptake into mitochondria during the active phase reduces the mitochondrial inner membrane potential, reducing the rate of production of ATP, which in turn activates the K-ATP current and re polarizes the plasma membrane.