CALCIUM OSCILLATIONS IN PITUITARY GONADOTROPHS - COMPARISON OF EXPERIMENT AND THEORY

We have developed a mathematical model that describes several aspects of agonist-induced Ca2+ signaling in single pituitary gonadotrophs. Ou r model is based on fast activation of the inositol 1,4,5-trisphosphat e (InsP3) receptor Ca2+ channels at low free cytosolic Ca2+ concentrat ion ([Ca2+]i) and slow inactivation at high [Ca2+]i. Previous work has shown that these gating properties, when combined with a Ca2+-ATPase, are sufficient to generate simulated Ca2+ oscillations. The Hodgkin-H uxley-like description we formulate here incorporates these different gating properties explicitly and renders their effects transparent and easy to modulate. We introduce regulatory mechanisms of channel openi ng which enable the model, both in the absence and in the presence of Ca2+ entry, to give responses to a wide range of agonist doses that ar e in good agreement with experimental findings, including subthreshold responses, superthreshold oscillations with frequency determined by [ InsP3], and nonoscillatory ''biphasic'' responses followed occasionall y by small-amplitude oscillations. A particular added feature of our m odel, enhanced channel opening by reduced concentration of Ca2+ in the lumen of the endoplasmic reticulum, allows oscillations to continue d uring pool depletion. The model predicts that ionomycin and thapsigarg in can induce oscillations with basal [InsP3] and zero Ca2+ entry, whi le Ca2+ injection cannot. Responses to specific pairings of sub- or su perthreshold stimuli of agonist, ionomycin, and thapsigargin are also correctly predicted. Since this model encompasses a wide range of obse rved dynamic behaviors within a single framework, based on well-establ ished mechanisms, its relevance should not be restricted to gonadotrop hs.