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 Ca2+ by InsP3 (Muallem et al., J. biol. Chem. 264, 205-212 (1989)) has been put forward in which intraluminal Ca2+ levels modulate Ins-P3 receptor structure (Irvine,FEBS Lett. 263, 5-9 (1990)). Here we have modelled such a steady-state mechanism, with an InsP3-sensitive store plus an InsP3-insensitive one, to test its ability to mimic published data. We have also performed experiments on InsP3-stimulated rat liver microsomes to test whether the model is consistent with one-way Ca2+ fluxes at a steady state. The model can simulate quantal release, in that InsP3 produces a release of part of the stored Ca2+ which is initially rapid relative to the one-way flux. In the original form of the model, in which InsP3-modulated Ca2+ binding to the intraluminal site opens the Ca2+ channel, the range of InsP3 concentrations needed to release Ca2+ is greater than that observed. When the model is changed so that Ca2+-modulated InsP3 binding opens the channels, the effective InsP3 range is shortened, but the quantal release effect is reduced. Other published data on oneway fluxes, and our own data on microsomes, can be simulated when leakage from the InsP3-insensitive store is adjusted to fit the observations; these data therefore do not test the existence of a steady state in the InsP3-sensitive store. We conclude that sensitivity of Ca2+ release to intraluminal Ca2+ 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.