Agonist-specificity in the role of Ca(2+)-induced Ca2+ release in hepatocyte Ca2+ oscillations

Ca(2+)-mobilizing hormones induce oscillations in the cytoplasmic concentration of free Ca2+ ('free Ca') (spikes) in many cells. In hepatocytes the frequency of spiking depends on agonist dose, but the time course of an individual spike does not change with agonist concentration. Interestingly, the time course of individual spikes does depend on the hormone species, but the cellular mechanisms underlying this agonist-specificity are not understood. Here we show that ryanodine, which blocks the muscle Ca2+ channel responsible for Ca(2+)-induced Ca2+ release ('CICR') in the open conformation, has almost no effect on phenylephrine-induced spikes, but does, in contrast, inhibit vasopressin- or angiotensin II-induced spikes. We also show that ryanodine has no effect either on the increase in frequency or on the elevated peak free Ca induced by increased cyclic AMP on phenylephrine spikes. In contrast, ryanodine truncates the prolonged falling phases of spikes induced by vasopressin or angiotensin II in the presence of elevated cyclic AMP. A working hypothesis is proposed in which vasopressin- or angiotensin II-induced spikes consist of an Ins(1,4,5)P3-mediated symmetrical spike, identical in time course and mechanism with those induced by phenylephrine, followed by a 'tail' that represents CICR. The data hint at the existence of a novel signalling pathway.