EFFECT OF VOLTAGE-GATED PLASMA-MEMBRANE CA2+ FLUXES ON IP(3)-LINKED CA2+ OSCILLATIONS

We present a theoretical investigation of the effect of Ca2+ influx through ion channels in the plasma membrane on Ca2+ oscillations induced by agonist stimulation of Ca2+ release from internal stores. We expand a recent model of internal Ca2+ oscillations based on activation and inhibition of the IP3-receptor in the endoplasmic reticulum by introducing plasma membrane voltage-gated Ca2+ and K+ channels based on patch-clamp experiments on mouse pancreatic beta cells. Simulations of voltage- and current-clamped experiments are carried out. The amplitude and frequency of the oscillations as well as the sensitivity to agonist are strongly affected by altering the value of the voltage-clamp. We show that the fundamental quantity governing voltage clamp measurements is the inward flux of Ca2+, which acts as a control parameter to alter characteristics of the oscillations. Under current clamp conditions (I(applied) = 0) that lead to continuous spiking electrical activity, we examine the couping between electrical activity and Ca2+ by introducing a small whole cell Ca2+-activated K+ conductance. Results of calculations are similar to those observed in agonist-stimulated beta cells and gonadotrophs. We conclude, however, that glucose-induced bursting and agonist induced bursting in beta cells are distinct phenomena and suggest a mechanism by which agonist-induced Ca2+ oscillations might potentiate insulin secretion. This leads to a general principle for selective signal transduction by Ca2+ oscillations.