Journal
CELL REPORTS
Volume 9, Issue 4, Pages 1209-1218Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2014.10.033
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Funding
- NIH [DK082954, AA017752]
- Thomas P. Infusion Endowed Chair
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Receptor-mediated oscillations in cytosolic Ca2+ concentration ([Ca2+](i)) could originate either directly from an autonomous Ca2+ feedback oscillator at the inositol 1,4,5-trisphosphate (IP3) receptor or as a secondary consequence of IP3 oscillations driven by Ca2+ feedback on IP3 metabolism. It is challenging to discriminate these alternatives, because IP3 fluctuations could drive Ca2+ oscillations or could just be a secondary response to the [Ca2+](i) spikes. To investigate this problem, we constructed a recombinant IP3 buffer using type-I IP3 receptor ligand-binding domain fused to GFP (GFP-LBD), which buffers IP3 in the physiological range. This IP3 buffer slows hormone-induced [IP3] dynamics without changing steady-state [IP3]. GFP-LBD perturbed [Ca2+](i) oscillations in a dose-dependent manner: it decreased both the rate of [Ca2+](i) rise and the speed of Ca2+ wave propagation and, at high levels, abolished [Ca2+](i) oscillations completely. These data, together with computational modeling, demonstrate that IP3 dynamics play a fundamental role in generating [Ca2+](i) oscillations and waves.
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