%0 Journal Article %1 Sobi_2002_59 %A Sobie, Eric A %A Dilly, Keith W %A dos Santos Cruz, Jader %A Lederer, W. Jonathan %A Jafri, M. Saleet %D 2002 %J Biophys. J. %K 12080100 Agents, Animals, Biological, Calci, Calcium Calcium, Cardiac, Carlo Channel, Channels, Confocal, Congestive, Factors, Failure, Fluorescence, Gov't, Guinea Heart Immunosuppressive Kinetics, L-Type, Method, Mice, Microscopy, Models, Monte Myocardium, Myocytes, P.H.S., Pigs, Rats, Receptor Release Research Reticulum, Ryanodine Sarcoplasmic Signal Signaling, Sirolimus, Support, Tacrolimus, Temperature, Theoretical, Time Transduction, U.S. um, %N 1 %P 59--78 %T Termination of cardiac Ca$^2+$ sparks: an investigative mathematical model of calcium-induced calcium release. %U http://www.biophysj.org/cgi/content/full/83/1/59 %V 83 %X A Ca$^2+$ spark arises when a cluster of sarcoplasmic reticulum (SR) channels (ryanodine receptors or RyRs) opens to release calcium in a locally regenerative manner. Normally triggered by Ca$^2+$ influx across the sarcolemmal or transverse tubule membrane neighboring the cluster, the Ca$^2+$ spark has been shown to be the elementary Ca$^2+$ signaling event of excitation-contraction coupling in heart muscle. However, the question of how the Ca$^2+$ spark terminates remains a central, unresolved issue. Here we present a new model, "sticky cluster," of SR Ca$^2+$ release that simulates Ca$^2+$ spark behavior and enables robust Ca$^2+$ spark termination. Two newly documented features of RyR behavior have been incorporated in this otherwise simple model: "coupled gating" and an opening rate that depends on SR lumenal Ca$^2+$. Using a Monte Carlo method, local Ca$^2+$-induced Ca$^2+$ release from clusters containing between 10 and 100 RyRs is modeled. After release is triggered, Ca$^2+$ flux from RyRs diffuses into the cytosol and binds to intracellular buffers and the fluorescent Ca$^2+$ indicator fluo-3 to produce the model Ca$^2+$ spark. Ca$^2+$ sparks generated by the sticky cluster model resemble those observed experimentally, and Ca$^2+$ spark duration and amplitude are largely insensitive to the number of RyRs in a cluster. As expected from heart cell investigation, the spontaneous Ca$^2+$ spark rate in the model increases with elevated cytosolic or SR lumenal Ca$^2+$. Furthermore, reduction of RyR coupling leads to prolonged model Ca$^2+$ sparks just as treatment with FK506 lengthens Ca$^2+$ sparks in heart cells. This new model of Ca$^2+$ spark behavior provides a "proof of principle" test of a new hypothesis for Ca$^2+$ spark termination and reproduces critical features of Ca$^2+$ sparks observed experimentally.

@article{Sobi_2002_59, abstract = {A {C}a$^{2+}$ spark arises when a cluster of sarcoplasmic reticulum (SR) channels (ryanodine receptors or RyRs) opens to release calcium in a locally regenerative manner. Normally triggered by {C}a$^{2+}$ influx across the sarcolemmal or transverse tubule membrane neighboring the cluster, the {C}a$^{2+}$ spark has been shown to be the elementary {C}a$^{2+}$ signaling event of excitation-contraction coupling in heart muscle. However, the question of how the {C}a$^{2+}$ spark terminates remains a central, unresolved issue. Here we present a new model, "sticky cluster," of SR {C}a$^{2+}$ release that simulates {C}a$^{2+}$ spark behavior and enables robust {C}a$^{2+}$ spark termination. Two newly documented features of RyR behavior have been incorporated in this otherwise simple model: "coupled gating" and an opening rate that depends on SR lumenal [{C}a$^{2+}$]. Using a Monte Carlo method, local {C}a$^{2+}$-induced {C}a$^{2+}$ release from clusters containing between 10 and 100 RyRs is modeled. After release is triggered, {C}a$^{2+}$ flux from RyRs diffuses into the cytosol and binds to intracellular buffers and the fluorescent {C}a$^{2+}$ indicator fluo-3 to produce the model {C}a$^{2+}$ spark. {C}a$^{2+}$ sparks generated by the sticky cluster model resemble those observed experimentally, and {C}a$^{2+}$ spark duration and amplitude are largely insensitive to the number of RyRs in a cluster. As expected from heart cell investigation, the spontaneous {C}a$^{2+}$ spark rate in the model increases with elevated cytosolic or SR lumenal [{C}a$^{2+}$]. Furthermore, reduction of RyR coupling leads to prolonged model {C}a$^{2+}$ sparks just as treatment with FK506 lengthens {C}a$^{2+}$ sparks in heart cells. This new model of {C}a$^{2+}$ spark behavior provides a "proof of principle" test of a new hypothesis for {C}a$^{2+}$ spark termination and reproduces critical features of {C}a$^{2+}$ sparks observed experimentally.}, added-at = {2009-06-03T11:20:58.000+0200}, author = {Sobie, Eric A and Dilly, Keith W and dos Santos Cruz, Jader and Lederer, W. Jonathan and Jafri, M. Saleet}, biburl = {https://www.bibsonomy.org/bibtex/21cb16989ecd9baf9f136e0f154befa8f/hake}, description = {The whole bibliography file I use.}, file = {Sobi_2002_59.pdf:Sobi_2002_59.pdf:PDF}, interhash = {a8d7ee86a1de7740fd57c4cb3f3d7e75}, intrahash = {1cb16989ecd9baf9f136e0f154befa8f}, journal = {Biophys. J.}, key = 95, keywords = {12080100 Agents, Animals, Biological, Calci, Calcium Calcium, Cardiac, Carlo Channel, Channels, Confocal, Congestive, Factors, Failure, Fluorescence, Gov't, Guinea Heart Immunosuppressive Kinetics, L-Type, Method, Mice, Microscopy, Models, Monte Myocardium, Myocytes, P.H.S., Pigs, Rats, Receptor Release Research Reticulum, Ryanodine Sarcoplasmic Signal Signaling, Sirolimus, Support, Tacrolimus, Temperature, Theoretical, Time Transduction, U.S. um,}, month = Jul, number = 1, pages = {59--78}, pmid = {12080100}, timestamp = {2009-06-03T11:21:31.000+0200}, title = {Termination of cardiac {C}a$^{2+}$ sparks: an investigative mathematical model of calcium-induced calcium release.}, url = {http://www.biophysj.org/cgi/content/full/83/1/59}, volume = 83, year = 2002 }