Transient inositol 1,4,5-trisphosphate-induced Ca2+ release: a model based on regulatory Ca(2+)-binding sites along the permeation pathway.

A remarkable property of Ca2+ fluxes through the inositol 1,4,5-trisphosphate (InsP3)-gated Ca2+ channel is that successive increments of InsP3 induce repeated transient release of accumulated Ca2+. The initial aim of this study was to propose a model, based on hypotheses compatible with the current description of this Ca2+ channel, which could account for such experimental observations. The key feature of the model was the assumption that the Ca(2+)-binding sites on the receptor, whose occupancy leads to immediate channel activation but to subsequent slow channel desensitization, were located somewhere along the permeation pathway and were therefore sensitive to the flux of Ca2+ rather than the cytosolic or luminal Ca2+ concentration per se. Simulation showed that, provided Ca2+ bound to both activating and inhibitory sites with adequate cooperativity, addition of submaximal concentrations InsP3 resulted in transient opening well above the stationary state. The model also rationalized the documented existence of a threshold for InsP3 action, the puzzling control of channel sensitivity to InsP3 by luminal and cytosolic Ca2+, as well as the functional heterogeneity of the Ca2+ pools.