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

Inositol-1,4,5-trisphosphate (InsP3)-induced Ca2+ release is a key mechanism for intracellular Ca2+ mobilization. The rate of Ca2+ release declines progressively with time until a higher concentration of InsP3 is added, which is referred to as the incremental detection mechanism. 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. We studied this phenomenon by real-time measurement of the luminal Ca2+ concentration of Ca2+ stores using a Ca(2+)-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.