Hormone-Induced Calcium Oscillations Depend on Cross-Coupling with Inositol 1,4,5-Trisphosphate Oscillations

摘要

Receptor-mediated oscillations in cytosolic Ca^2^+ concentration ([Ca^2^+]"i) could originate either directly from an autonomous Ca^2^+ feedback oscillator at the inositol 1,4,5-trisphosphate (IP"3) receptor or as a secondary consequence of IP"3 oscillations driven by Ca^2^+ feedback on IP"3 metabolism. It is challenging to discriminate these alternatives, because IP"3 fluctuations could drive Ca^2^+ oscillations or could just be a secondary response to the [Ca^2^+]"i spikes. To investigate this problem, we constructed a recombinant IP"3 buffer using type-I IP"3 receptor ligand-binding domain fused to GFP (GFP-LBD), which buffers IP"3 in the physiological range. This IP"3 buffer slows hormone-induced [IP"3] dynamics without changing steady-state [IP"3]. GFP-LBD perturbed [Ca^2^+]"i oscillations in a dose-dependent manner: it decreased both the rate of [Ca^2^+]"i rise and the speed of Ca^2^+ wave propagation and, at high levels, abolished [Ca^2^+]"i oscillations completely. These data, together with computational modeling, demonstrate that IP"3 dynamics play a fundamental role in generating [Ca^2^+]"i oscillations and waves.