Heterogeneity of channel density in inositol-1,4,5-trisphosphate-sensitive Ca²⁺ stores

Abstract

lNOSiTOL-l,4,5-trisphosphate (InsP₃)-induced Ca²⁺ release is a key mechanism for intracellular Ca²⁺ mobilization¹. The rate of Ca²⁺ release declines progressively with time until a higher concen-tration of InsP₃ is added, which is referred to as the incremental detection mechanism². Two hypotheses have been postulated to explain these complex kinetics: (1) Ca²⁺ stores consist of multiple compartments (quanta) with different sensitivities to InsP3 (refs 3-7), and (2) the rate of Ca²⁺ release is modulated by the Ca²⁺ concentration in the lumen of Ca²⁺ stores^8–12. We studied this phenomenon by real-time measurement of the luminal Ca²⁺ con-centration of Ca²⁺ stores using a Ca²⁺-sensitive fluorescent dye, but our results were not explained by either of these hypotheses. Here we report that the complex kinetics of Ca²⁺ release results from the heterogeneous density of equally InsP3-sensitive channels on the Ca²⁺ stores. This heterogeneity creates Ca²⁺ stores with apparently different sensitivities to InsP₃, which may have different functions in Ca²⁺ mobilization.