A re-evaluation of the apparent effects of luminal Ca2+ on inositol 1,4,5-trisphosphate-induced Ca2+ release

It has been suggested that the release of Ca2+ from intracellular stores by inositol 1,4,5-trisphosphate (InsP3) is modulated by the luminal Ca2+ content of the stores and that such an effect could underlie the apparent 'quantal' nature of InsP3-induced release. Although initial studies failed to find evidence in support of such a modulation, several subsequent reports have indicated luminal Ca2+ effects that become apparent only after a greater than 70-75% depletion of Ca2+ stores. In these studies, Ca2+ release was expressed as a percentage of an A23187-releasable pool which comprised both InsP3-sensitive and InsP3-insensitive components. In model calculations we have found that the presence of even a minor InsP3-insensitive component in the total Ca2+ pool significantly distorts interpretation of the data. We show that the published results can be accurately duplicated without any requirement for a shift in the true InsP3 sensitivity of Ca2+ release if either: (a) the InsP3-insensitive component does not remain a constant proportion of the total pool during depletion (i.e. depletion disproportionally affects the InsP3-sensitive component); or (b) during generation of InsP3-response curves, additional Ca2+ is released from the InsP3-insensitive component as the InsP3-sensitive component is progressively emptied. Examination indicates that either, or both, of these conditions apply in the published reports and we conclude that the demonstrated effects of luminal Ca2+ may be artifacts.