Hormone-Induced Calcium Oscillations Depend on Cross-Coupling with Inositol 1,4,5-Trisphosphate Oscillations
Lawrence D. Gaspers,
Paula J. Bartlett,
Antonio Politi,
Paul Burnett,
Walson Metzger,
Jane Johnston,
Suresh K. Joseph,
Thomas Höfer,
Andrew P. Thomas
Affiliations
Lawrence D. Gaspers
Department of Pharmacology and Physiology, New Jersey Medical School, Rutgers, The State University of New Jersey, 185 South Orange Avenue, Newark, NJ 07103, USA
Paula J. Bartlett
Department of Pharmacology and Physiology, New Jersey Medical School, Rutgers, The State University of New Jersey, 185 South Orange Avenue, Newark, NJ 07103, USA
Antonio Politi
German Cancer Research Center, Division of Theoretical Systems Biology, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
Paul Burnett
Department of Pharmacology and Physiology, New Jersey Medical School, Rutgers, The State University of New Jersey, 185 South Orange Avenue, Newark, NJ 07103, USA
Walson Metzger
Department of Pharmacology and Physiology, New Jersey Medical School, Rutgers, The State University of New Jersey, 185 South Orange Avenue, Newark, NJ 07103, USA
Jane Johnston
Department of Pharmacology and Physiology, New Jersey Medical School, Rutgers, The State University of New Jersey, 185 South Orange Avenue, Newark, NJ 07103, USA
Suresh K. Joseph
Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, 1020 Locust Street, Philadelphia, PA 19107, USA
Thomas Höfer
German Cancer Research Center, Division of Theoretical Systems Biology, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
Andrew P. Thomas
Department of Pharmacology and Physiology, New Jersey Medical School, Rutgers, The State University of New Jersey, 185 South Orange Avenue, Newark, NJ 07103, USA
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.
