{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T15:53:33Z","timestamp":1776873213134,"version":"3.51.2"},"reference-count":56,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2016,1,5]],"date-time":"2016-01-05T00:00:00Z","timestamp":1451952000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"DOI":"10.1371\/journal.pcbi.1004671","type":"journal-article","created":{"date-parts":[[2016,1,5]],"date-time":"2016-01-05T19:06:10Z","timestamp":1452020770000},"page":"e1004671","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":29,"title":["Long-Lasting Sparks: Multi-Metastability and Release Competition in the Calcium Release Unit Network"],"prefix":"10.1371","volume":"12","author":[{"given":"Zhen","family":"Song","sequence":"first","affiliation":[]},{"given":"Alain","family":"Karma","sequence":"additional","affiliation":[]},{"given":"James N.","family":"Weiss","sequence":"additional","affiliation":[]},{"given":"Zhilin","family":"Qu","sequence":"additional","affiliation":[]}],"member":"340","published-online":{"date-parts":[[2016,1,5]]},"reference":[{"key":"ref1","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1038\/35036035","article-title":"The versatility and universality of calcium signalling","volume":"1","author":"MJ Berridge","year":"2000","journal-title":"Nat Rev Mol Cell Biol"},{"key":"ref2","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1038\/27094","article-title":"Calcium\u2014a life and death signal","volume":"395","author":"MJ Berridge","year":"1998","journal-title":"Nature"},{"key":"ref3","doi-asserted-by":"crossref","first-page":"1047","DOI":"10.1016\/j.cell.2007.11.028","article-title":"Calcium signaling","volume":"131","author":"DE Clapham","year":"2007","journal-title":"Cell"},{"key":"ref4","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1161\/CIRCRESAHA.109.206078","article-title":"A coupled system of intracellular Ca2+ clocks and surface membrane voltage clocks controls the timekeeping mechanism of the heart&apos;s pacemaker","volume":"106","author":"EG Lakatta","year":"2010","journal-title":"Circ Res"},{"key":"ref5","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.physrep.2014.05.002","article-title":"Nonlinear and stochastic dynamics in the heart","volume":"543","author":"Z Qu","year":"2014","journal-title":"Physics Reports"},{"key":"ref6","doi-asserted-by":"crossref","first-page":"1491","DOI":"10.1152\/physrev.00030.2007","article-title":"Calcium Sparks","volume":"88","author":"H Cheng","year":"2008","journal-title":"Physiol Rev"},{"key":"ref7","doi-asserted-by":"crossref","first-page":"e1000870","DOI":"10.1371\/journal.pcbi.1000870","article-title":"Calcium signals driven by single channel noise","volume":"6","author":"A Skupin","year":"2010","journal-title":"PLoS Comput Biol"},{"key":"ref8","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1088\/1478-3967\/1\/1\/003","article-title":"Cooperativity can reduce stochasticity in intracellular calcium dynamics","volume":"1","author":"K Wang","year":"2004","journal-title":"Phys Biol"},{"key":"ref9","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1073\/pnas.0236032100","article-title":"Optimal ion channel clustering for intracellular calcium signaling","volume":"100","author":"JW Shuai","year":"2003","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref10","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/S0006-3495(03)74831-0","article-title":"On the role of stochastic channel behavior in intracellular Ca2+ dynamics","volume":"84","author":"M Falcke","year":"2003","journal-title":"Biophys J"},{"key":"ref11","doi-asserted-by":"crossref","first-page":"2433","DOI":"10.1016\/j.bpj.2012.05.001","article-title":"Criticality in intracellular calcium signaling in cardiac myocytes","volume":"102","author":"M Nivala","year":"2012","journal-title":"Biophys J"},{"key":"ref12","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.yjmcc.2014.12.024","article-title":"Acute reversal of phospholamban inhibition facilitates the rhythmic whole-cell propagating calcium waves in isolated ventricular myocytes","volume":"80","author":"Y-H Chan","year":"2015","journal-title":"Journal of Molecular and Cellular Cardiology"},{"key":"ref13","doi-asserted-by":"crossref","first-page":"5670","DOI":"10.1073\/pnas.0511061103","article-title":"Turing instability mediated by voltage and calcium diffusion in paced cardiac cells","volume":"103","author":"Y Shiferaw","year":"2006","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref14","doi-asserted-by":"crossref","first-page":"3767","DOI":"10.1529\/biophysj.108.130419","article-title":"Calsequestrin-mediated mechanism for cellular calcium transient alternans","volume":"95","author":"JG Restrepo","year":"2008","journal-title":"Biophys J"},{"key":"ref15","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1161\/CIRCRESAHA.109.197590","article-title":"Dynamical mechanism for subcellular alternans in cardiac myocytes","volume":"105","author":"SA Gaeta","year":"2009","journal-title":"Circ Res"},{"key":"ref16","doi-asserted-by":"crossref","first-page":"1908","DOI":"10.1016\/j.bpj.2015.03.011","article-title":"Calcium-Voltage Coupling in the Genesis of Early and Delayed Afterdepolarizations in Cardiac Myocytes","volume":"108","author":"Z Song","year":"2015","journal-title":"Biophysical Journal"},{"key":"ref17","doi-asserted-by":"crossref","first-page":"108101","DOI":"10.1103\/PhysRevLett.114.108101","article-title":"Calcium alternans is due to an order-disorder phase transition in cardiac cells","volume":"114","author":"E Alvarez-Lacalle","year":"2015","journal-title":"Phys Rev Lett"},{"key":"ref18","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.yjmcc.2014.10.018","article-title":"T-tubule disruption promotes calcium alternans in failing ventricular myocytes: Mechanistic insights from computational modeling","volume":"79","author":"M Nivala","year":"2015","journal-title":"Journal of Molecular and Cellular Cardiology"},{"key":"ref19","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1126\/science.8235594","article-title":"Calcium sparks: elementary events underlying excitation-contraction coupling in heart muscle","volume":"262","author":"H Cheng","year":"1993","journal-title":"Science"},{"key":"ref20","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1113\/jphysiol.1997.sp022025","article-title":"The immunophilin FK506-binding protein modulates Ca2+ release channel closure in rat heart","volume":"500","author":"RP Xiao","year":"1997","journal-title":"The Journal of Physiology"},{"key":"ref21","doi-asserted-by":"crossref","first-page":"1192","DOI":"10.1161\/01.RES.83.12.1192","article-title":"Bay K 8644 increases resting Ca2+ spark frequency in ferret ventricular myocytes independent of Ca influx: contrast with caffeine and ryanodine effects","volume":"83","author":"H Satoh","year":"1998","journal-title":"Circ Res"},{"key":"ref22","doi-asserted-by":"crossref","first-page":"814","DOI":"10.1016\/S0006-3495(00)76338-7","article-title":"Effects of imperatoxin A on local sarcoplasmic reticulum Ca2+ release in frog skeletal muscle","volume":"79","author":"A Shtifman","year":"2000","journal-title":"Biophysical Journal"},{"key":"ref23","doi-asserted-by":"crossref","first-page":"4380","DOI":"10.1073\/pnas.070056497","article-title":"Involvement of multiple intracellular release channels in calcium sparks of skeletal muscle","volume":"97","author":"A Gonzalez","year":"2000","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref24","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1529\/biophysj.103.031435","article-title":"Effects of Ryanoids on Spontaneous and Depolarization-Evoked Calcium Release Events in Frog Muscle","volume":"87","author":"CS Hui","year":"2004","journal-title":"Biophysical Journal"},{"key":"ref25","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1085\/jgp.115.2.139","article-title":"The spark and its ember: separately gated local components of Ca(2+) release in skeletal muscle","volume":"115","author":"A Gonzalez","year":"2000","journal-title":"J Gen Physiol"},{"key":"ref26","doi-asserted-by":"crossref","first-page":"e105","DOI":"10.1161\/CIRCRESAHA.107.183236","article-title":"Termination of cardiac Ca2+ sparks: role of intra-SR [Ca2+], release flux, and intra-SR Ca2+ diffusion","volume":"103","author":"AV Zima","year":"2008","journal-title":"Circ Res"},{"key":"ref27","doi-asserted-by":"crossref","first-page":"1867","DOI":"10.1529\/biophysj.107.114694","article-title":"Partial inhibition of sarcoplasmic reticulum ca release evokes long-lasting ca release events in ventricular myocytes: role of luminal ca in termination of ca release","volume":"94","author":"AV Zima","year":"2008","journal-title":"Biophys J"},{"key":"ref28","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1161\/01.RES.0000151841.63705.01","article-title":"Characteristics of Prolonged Ca2+ Release Events Associated With the Nuclei in Adult Cardiac Myocytes","volume":"96","author":"Z Yang","year":"2005","journal-title":"Circulation Research"},{"key":"ref29","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.1161\/hh1101.091268","article-title":"Coupled Gating Between Cardiac Calcium Release Channels (Ryanodine Receptors)","volume":"88","author":"SO Marx","year":"2001","journal-title":"Circulation Research"},{"key":"ref30","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/S0006-3495(02)75149-7","article-title":"Termination of cardiac Ca(2+) sparks: an investigative mathematical model of calcium-induced calcium release","volume":"83","author":"EA Sobie","year":"2002","journal-title":"Biophys J"},{"key":"ref31","doi-asserted-by":"crossref","first-page":"1293","DOI":"10.1016\/S0006-3495(04)74203-4","article-title":"A Mathematical Analysis of the Generation and Termination of Calcium Sparks","volume":"86","author":"R Hinch","year":"2004","journal-title":"Biophysical Journal"},{"key":"ref32","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1085\/jgp.201311034","article-title":"Life and death of a cardiac calcium spark","volume":"142","author":"MD Stern","year":"2013","journal-title":"J Gen Physiol"},{"key":"ref33","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/j.yjmcc.2009.10.005","article-title":"Flecainide inhibits arrhythmogenic Ca2+ waves by open state block of ryanodine receptor Ca2+ release channels and reduction of Ca2+ spark mass","volume":"48","author":"FA Hilliard","year":"2010","journal-title":"J Mol Cell Cardiol"},{"issue":"Pt 2","key":"ref34","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1113\/jphysiol.1997.sp022021","article-title":"Dual effects of tetracaine on spontaneous calcium release in rat ventricular myocytes","volume":"500","author":"S Gyorke","year":"1997","journal-title":"J Physiol"},{"key":"ref35","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1103\/RevModPhys.15.1","article-title":"Stochastic Problems in Physics and Astronomy","volume":"15","author":"S Chandrasekhar","year":"1943","journal-title":"Reviews of Modern Physics"},{"key":"ref36","doi-asserted-by":"crossref","first-page":"2068","DOI":"10.1016\/S0006-3495(97)78850-7","article-title":"Stochastic versions of the Hodgkin-Huxley equations","volume":"72","author":"RF Fox","year":"1997","journal-title":"Biophys J"},{"key":"ref37","doi-asserted-by":"crossref","first-page":"3723","DOI":"10.1529\/biophysj.104.049973","article-title":"A simplified local control model of calcium-induced calcium release in cardiac ventricular myocytes","volume":"87","author":"R Hinch","year":"2004","journal-title":"Biophys J"},{"key":"ref38","doi-asserted-by":"crossref","first-page":"114","DOI":"10.3389\/fphys.2012.00114","article-title":"Computational modeling and numerical methods for spatiotemporal calcium cycling in ventricular myocytes","volume":"3","author":"M Nivala","year":"2012","journal-title":"Front Physiol"},{"key":"ref39","article-title":"The Fokker-Plank Equation","author":"H Risken","year":"1989"},{"key":"ref40","doi-asserted-by":"crossref","first-page":"2904","DOI":"10.1016\/j.bpj.2011.05.031","article-title":"Multiscale modeling of calcium cycling in cardiac ventricular myocyte: macroscopic consequences of microscopic dyadic function","volume":"100","author":"N Gaur","year":"2011","journal-title":"Biophys J"},{"key":"ref41","doi-asserted-by":"crossref","first-page":"22275","DOI":"10.1073\/pnas.0908971106","article-title":"Optical single-channel resolution imaging of the ryanodine receptor distribution in rat cardiac myocytes","volume":"106","author":"D Baddeley","year":"2009","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref42","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1113\/jphysiol.2001.012940","article-title":"Intracellular [Na+] and Na+ pump rate in rat and rabbit ventricular myocytes","volume":"539","author":"S Despa","year":"2002","journal-title":"J Physiol"},{"key":"ref43","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1016\/S0006-3495(92)81615-6","article-title":"Theory of excitation-contraction coupling in cardiac muscle","volume":"63","author":"MD Stern","year":"1992","journal-title":"Biophys J"},{"key":"ref44","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1016\/j.ceca.2004.01.013","article-title":"Putting out the fire: what terminates calcium-induced calcium release in cardiac muscle?","volume":"35","author":"MD Stern","year":"2004","journal-title":"Cell Calcium"},{"key":"ref45","doi-asserted-by":"crossref","first-page":"2115","DOI":"10.1016\/j.bpj.2013.04.010","article-title":"Extinguishing the sparks","volume":"104","author":"RL Winslow","year":"2013","journal-title":"Biophys J"},{"key":"ref46","doi-asserted-by":"crossref","first-page":"15096","DOI":"10.1073\/pnas.95.25.15096","article-title":"Termination of Ca2+ release by a local inactivation of ryanodine receptors in cardiac myocytes","volume":"95","author":"JS Sham","year":"1998","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref47","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1016\/j.yjmcc.2011.06.024","article-title":"Dynamic local changes in sarcoplasmic reticulum calcium: physiological and pathophysiological roles","volume":"52","author":"EA Sobie","year":"2012","journal-title":"J Mol Cell Cardiol"},{"key":"ref48","doi-asserted-by":"crossref","first-page":"2801","DOI":"10.1016\/S0006-3495(98)77723-9","article-title":"Regulation of the cardiac ryanodine receptor channel by luminal Ca2+ involves luminal Ca2+ sensing sites","volume":"75","author":"I Gyorke","year":"1998","journal-title":"Biophys J"},{"key":"ref49","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1161\/CIRCRESAHA.111.240234","article-title":"Dynamic calcium movement inside cardiac sarcoplasmic reticulum during release","volume":"108","author":"E Picht","year":"2011","journal-title":"Circ Res"},{"key":"ref50","doi-asserted-by":"crossref","first-page":"2149","DOI":"10.1016\/j.bpj.2013.03.058","article-title":"Control of sarcoplasmic reticulum Ca2+ release by stochastic RyR gating within a 3D model of the cardiac dyad and importance of induction decay for CICR termination","volume":"104","author":"MB Cannell","year":"2013","journal-title":"Biophys J"},{"key":"ref51","doi-asserted-by":"crossref","first-page":"3018","DOI":"10.1016\/j.bpj.2014.11.003","article-title":"Superresolution Modeling of Calcium Release in the Heart","volume":"107","author":"M A Walker","year":"2014","journal-title":"Biophysical Journal"},{"key":"ref52","doi-asserted-by":"crossref","first-page":"4403","DOI":"10.1113\/jphysiol.2012.227926","article-title":"Modeling Cardiac Calcium Sparks in a Three-Dimensional Reconstruction of a Calcium Release Unit","volume":"590","author":"J Hake","year":"2012","journal-title":"J Physiol"},{"key":"ref53","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1007\/s00249-011-0755-7","article-title":"How does the ryanodine receptor in the ventricular myocyte wake up: by a single or by multiple open L-type Ca2+ channels?","volume":"41","author":"T Schendel","year":"2012","journal-title":"Eur Biophys J"},{"key":"ref54","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1016\/S0006-3495(94)80500-4","article-title":"Effects of rapid buffers on Ca2+ diffusion and Ca2+ oscillations","volume":"67","author":"J Wagner","year":"1994","journal-title":"Biophys J"},{"key":"ref55","doi-asserted-by":"crossref","first-page":"037115","DOI":"10.1063\/1.3207835","article-title":"Spatiotemporal intracellular calcium dynamics during cardiac alternans","volume":"19","author":"JG Restrepo","year":"2009","journal-title":"Chaos"},{"issue":"Pt 3","key":"ref56","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1111\/j.1469-7793.1999.00575.x","article-title":"Ca2+ sparks and Ca2+ waves in saponin-permeabilized rat ventricular myocytes","volume":"521","author":"V Lukyanenko","year":"1999","journal-title":"J Physiol"}],"container-title":["PLOS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/dx.plos.org\/10.1371\/journal.pcbi.1004671","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,5,9]],"date-time":"2020-05-09T11:06:03Z","timestamp":1589022363000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1004671"}},"subtitle":[],"editor":[{"given":"Jeffrey J.","family":"Saucerman","sequence":"first","affiliation":[]}],"short-title":[],"issued":{"date-parts":[[2016,1,5]]},"references-count":56,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2016,1,5]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1004671","relation":{},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,1,5]]}}}