A REEVALUATION 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 2+ inositol 1,4,5-trisphosphate (InsP(3)) is modulated by the luminal Ca2+ content of the stores and that such an effect could underlie the apparent 'quantal' nature of InsP(3)-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 InsP(3)-sensitive and InsP(3)-insensitive components, In model calculations we have found that the presence of even a minor InsP(3)-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 InsP(3) sensitivity of Ca2+ release if either: (a) the InsP(3)-insensitive component does not remain a constant proportion of the total pool during depletion (i.e. depletion disproportionally affects the InsP(3)-sensitive component); or (b) during generation of InsP(3)-response curves, additional Ca2+ is released from the InsP(3)-insensitive component as the InsP(3)-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.