Quantal release of Ca2+ from intracellular stores by InsP3: tests of the concept of control of Ca2+ release by intraluminal Ca2+

A possible mechanism for the generation of `quantal' release of intracellular Ca$^{2+}$ by InsP$\_{3}$ (Muallem et al., J. biol. Chem. 264, 205-212 (1989)) has been put forward in which intraluminal Ca$^{2+}$ levels modulate InsP$\_{3}$ receptor structure (Irvine, FEBS Lett. 263, 5-9 (1990)). Here we have modelled such a steady-state mechanism, with an InsP$\_{3}$-sensitive store plus an InsP$\_{3}$-insensitive one, to test its ability to mimic published data. We have also performed experiments on InsP$\_{3}$-stimulated rat liver microsomes to test whether the model is consistent with one-way Ca$^{2+}$ fluxes at a steady state. The model can simulate quantal release, in that InsP$\_{3}$ produces a release of part of the stored Ca$^{2+}$ which is initially rapid relative to the one-way flux. In the original form of the model, in which InsP$\_{3}$-modulated Ca$^{2+}$ binding to the intraluminal site opens the Ca$^{2+}$ channel, the range of InsP$\_{3}$ concentrations needed to release Ca$^{2+}$ is greater than that observed. When the model is changed so that Ca$^{2+}$-modulated InsP$\_{3}$ binding opens the channels, the effective InsP$\_{3}$ range is shortened, but the quantal release effect is reduced. Other published data on one-way fluxes, and our own data on microsomes, can be simulated when leakage from the InsP$\_{3}$-insensitive store is adjusted to fit the observations; these data therefore do not test the existence of a steady state in the InsP$\_{3}$-sensitive store. We conclude that sensitivity of Ca$^{2+}$ release to intraluminal Ca$^{2+}$ provides a steady-state explanation of most, but not all, current quantal release observations. More critical kinetic tests of its validity are proposed and possible modifications to its premises are discussed.