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-cell mitochondrial calcium handling and electrical
activity. I. Cytoplasmic variables
1 Institute of Theoretical Dynamics and 2 Section on Neurobiology, Physiology, and Behavior, University of California, Davis, California 95616
We continue our development of a kinetic
model of bursting electrical activity in the pancreatic 
-cell
( J. Keizer and G. Magnus. Biophys. J. 56: 229-242,
1989), including the influence of Ca2+ handling by the
mitochondria. Our minimal model of mitochondrial Ca2+
handling [G. Magnus and J. Keizer. Am. J. Physiol. 273 (Cell Physiol. 42): C717-C733, 1997] is expanded to
include the D-glucose dependence of the rate of production
of mitochondrial reducing equivalents. The Ca2+ dependence
of the mitochondrial dehydrogenases, which is also included in the
model, plays only a small role in the simulations, since the
dehydrogenases appear to be maximally activated when D-glucose concentrations are sufficient to produce
bursting. A previous model of ionic currents in the plasma membrane is
updated using a recent experimental characterization of the dependence of the conductance of the ATP-sensitive K+
(KATP) current on adenine nucleotides. The resulting
whole cell model is complex, involving 12 dynamic variables that couple
Ca2+ handling in the cytoplasm and the mitochondria with
electrical activity in the plasma and inner mitochondrial membranes.
Simulations with the whole cell model give rise to bursting electrical
activity similar to that seen in pancreatic islets and clusters of
pancreatic -cells. The full D-glucose dose response of
electrical activity is obtained if the cytosolic rate of ATP hydrolysis
is a sigmoidal function of glucose. The simulations give the correct
shape, period, and phase of the associated oscillations in cytosolic
Ca2+, predict that the conductance of the KATP
current oscillates out of phase with electrical activity [as recently
observed in ob/ob mice (O. Larsson, H. Kindmark, R. Bränstrom, B. Fredholm, and P.-O. Berggren. Proc. Natl. Acad.
Sci. USA 93: 5161-5165, 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 KATP current and
repolarizes the plasma membrane.
pancreatic -cell; electrical activity; adenosine
triphosphate-sensitive potassium channel
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