title: Ryanodine receptor gating controls generation of diastolic calcium waves in cardiac myocytes.
abstract: The role of cardiac ryanodine receptor (RyR) gating in the initiation and propagation of calcium waves was investigated using a mathematical model comprising a stochastic description of RyR gating and a deterministic description of calcium diffusion and sequestration. We used a one-dimensional array of equidistantly spaced RyR clusters, representing the confocal scanning line, to simulate the formation of calcium sparks. Our model provided an excellent description of the calcium dependence of the frequency of diastolic calcium sparks and of the increased tendency for the production of calcium waves after a decrease in cytosolic calcium buffering. We developed a hypothesis relating changes in the propensity to form calcium waves to changes of RyR gating and tested it by simulation. With a realistic RyR gating model, increased ability of RyR to be activated by Ca2+ strongly increased the propensity for generation of calcium waves at low (0.05-0.1-µM) calcium concentrations but only slightly at high (0.2-0.4-µM) calcium concentrations. Changes in RyR gating altered calcium wave formation by changing the calcium sensitivity of spontaneous calcium spark activation and/or the average number of open RyRs in spontaneous calcium sparks. Gating changes that did not affect RyR activation by Ca2+ had only a weak effect on the propensity to form calcium waves, even if they strongly increased calcium spark frequency. Calcium waves induced by modulating the properties of the RyR activation site could be suppressed by inhibiting the spontaneous opening of the RyR. These data can explain the increased tendency for production of calcium waves under conditions when RyR gating is altered in cardiac diseases.
authors.affiliation: Department of Physical and Theoretical Chemistry, Faculty of Natural Sciences, Comenius University, 842 15 Bratislava, Slovak Republic.
authors.forename: Pavol
authors.initials: P
authors.lastname: Petrovič
authors.affiliation: Department of Physical and Theoretical Chemistry, Faculty of Natural Sciences, Comenius University, 842 15 Bratislava, Slovak Republic Department of Muscle Cell Research, Institute of Molecular Physiology and Genetics, Slovak Academy of Sciences, 833 34 Bratislava, Slovak Republic.
authors.forename: Ivan
authors.initials: I
authors.lastname: Valent
authors.affiliation: Department of Muscle Cell Research, Institute of Molecular Physiology and Genetics, Slovak Academy of Sciences, 833 34 Bratislava, Slovak Republic Institute of Electronics and Photonics, Faculty of Electrical Engineering and Information Technology, Slovak University of Technology, 812 19 Bratislava, Slovak Republic.
authors.forename: Elena
authors.initials: E
authors.lastname: Cocherová
authors.affiliation: Department of Muscle Cell Research, Institute of Molecular Physiology and Genetics, Slovak Academy of Sciences, 833 34 Bratislava, Slovak Republic.
authors.forename: Jana
authors.initials: J
authors.lastname: Pavelková
authors.affiliation: Department of Muscle Cell Research, Institute of Molecular Physiology and Genetics, Slovak Academy of Sciences, 833 34 Bratislava, Slovak Republic alexandra.zahradnikova@savba.sk.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Zahradníková
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D003198:Computer Simulation; D003971:Diastole; D006801:Humans; D015640:Ion Channel Gating; D008955:Models, Cardiovascular; D032383:Myocytes, Cardiac / Q000378:metabolism*; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D013269:Stochastic Processes; D013997:Time Factors
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel; D002118:Calcium