Multiscale Modeling of Calcium Cycling in Cardiac Ventricular Myocyte: Macroscopic Consequences of Microscopic Dyadic Function

Overview

Journal Biophys J

Publisher Cell Press

Specialty Biophysics

Date 2011 Jun 22

PMID 21689523

Citations 25

Authors

Namit Gaur

Yoram Rudy

Affiliations

Soon will be listed here.

Abstract

In cardiac ventricular myocytes, calcium (Ca) release occurs at distinct structures (dyads) along t-tubules, where L-type Ca channels (LCCs) appose sarcoplasmic reticulum (SR) Ca release channels (RyR2s). We developed a model of the cardiac ventricular myocyte that simulates local stochastic Ca release processes. At the local Ca release level, the model reproduces Ca spark properties. At the whole-cell level, the model reproduces the action potential, Ca currents, and Ca transients. Changes in microscopic dyadic properties (e.g., during detubulation in heart failure) affect whole-cell behavior in complex ways, which we investigated by simulating changes in the dyadic volume and number of LCCs/RyR2s in the dyad, and effects of calsequestrin (CSQN) as a Ca buffer (CSQN buffer) or a luminal Ca sensor (CSQN regulator). We obtained the following results: 1), Increased dyadic volume and reduced LCCs/RyR2s decrease excitation-contraction coupling gain and cause asynchrony of SR Ca release, and interdyad coupling partially compensates for the reduced synchrony. 2), Impaired CSQN buffer depresses Ca transients without affecting the synchrony of SR Ca release. 3), When CSQN regulator function is impaired, interdyad coupling augments diastolic Ca release activity to form Ca waves and long-lasting Ca release events.

Citing Articles

Role of ryanodine receptor cooperativity in Ca-wave-mediated triggered activity in cardiomyocytes.

Zhong M, Karma A J Physiol. 2024; 602(24):6745-6787.

PMID: 39565684 PMC: 11652246. DOI: 10.1113/JP286145.

Diversity of cells and signals in the cardiovascular system.

Grandi E, Navedo M, Saucerman J, Bers D, Chiamvimonvat N, Dixon R J Physiol. 2023; 601(13):2547-2592.

PMID: 36744541 PMC: 10313794. DOI: 10.1113/JP284011.

Modeling Calcium Cycling in the Heart: Progress, Pitfalls, and Challenges.

Qu Z, Yan D, Song Z Biomolecules. 2022; 12(11).

PMID: 36421700 PMC: 9687412. DOI: 10.3390/biom12111686.

Multi-Scale Computational Modeling of Spatial Calcium Handling From Nanodomain to Whole-Heart: Overview and Perspectives.

Colman M, Alvarez-Lacalle E, Echebarria B, Sato D, Sutanto H, Heijman J Front Physiol. 2022; 13:836622.

PMID: 35370783 PMC: 8964409. DOI: 10.3389/fphys.2022.836622.

Ca Release via IP Receptors Shapes the Cardiac Ca Transient for Hypertrophic Signaling.

Hunt H, Tilunaite A, Bass G, Soeller C, Roderick H, Rajagopal V Biophys J. 2020; 119(6):1178-1192.

PMID: 32871099 PMC: 7499065. DOI: 10.1016/j.bpj.2020.08.001.

References

Fabiato A . Time and calcium dependence of activation and inactivation of calcium-induced release of calcium from the sarcoplasmic reticulum of a skinned canine cardiac Purkinje cell. J Gen Physiol. 1985; 85(2):247-89. PMC: 2215800. DOI: 10.1085/jgp.85.2.247. View

Song L, Sobie E, McCulle S, Lederer W, Balke C, Cheng H . Orphaned ryanodine receptors in the failing heart. Proc Natl Acad Sci U S A. 2006; 103(11):4305-10. PMC: 1449688. DOI: 10.1073/pnas.0509324103. View

Cheng H, Lederer W, Cannell M . Calcium sparks: elementary events underlying excitation-contraction coupling in heart muscle. Science. 1993; 262(5134):740-4. DOI: 10.1126/science.8235594. View

Song L, Alcalai R, Arad M, Wolf C, Toka O, Conner D . Calsequestrin 2 (CASQ2) mutations increase expression of calreticulin and ryanodine receptors, causing catecholaminergic polymorphic ventricular tachycardia. J Clin Invest. 2007; 117(7):1814-23. PMC: 1904315. DOI: 10.1172/JCI31080. View

Smith G, Keizer J, Stern M, Lederer W, Cheng H . A simple numerical model of calcium spark formation and detection in cardiac myocytes. Biophys J. 1998; 75(1):15-32. PMC: 1299676. DOI: 10.1016/S0006-3495(98)77491-0. View

Wier W, Balke C . Ca(2+) release mechanisms, Ca(2+) sparks, and local control of excitation-contraction coupling in normal heart muscle. Circ Res. 1999; 85(9):770-6. DOI: 10.1161/01.res.85.9.770. View

Zima A, Picht E, Bers D, Blatter L . Termination of cardiac Ca2+ sparks: role of intra-SR [Ca2+], release flux, and intra-SR Ca2+ diffusion. Circ Res. 2008; 103(8):e105-15. PMC: 2678058. DOI: 10.1161/CIRCRESAHA.107.183236. View

Sobie E, Dilly K, Cruz J, Lederer W, Jafri M . Termination of cardiac Ca(2+) sparks: an investigative mathematical model of calcium-induced calcium release. Biophys J. 2002; 83(1):59-78. PMC: 1302127. DOI: 10.1016/s0006-3495(02)75149-7. View

Sah R, Ramirez R, Backx P . Modulation of Ca(2+) release in cardiac myocytes by changes in repolarization rate: role of phase-1 action potential repolarization in excitation-contraction coupling. Circ Res. 2002; 90(2):165-73. DOI: 10.1161/hh0202.103315. View

10.

Dirksen W, Lacombe V, Chi M, Kalyanasundaram A, Viatchenko-Karpinski S, Terentyev D . A mutation in calsequestrin, CASQ2D307H, impairs Sarcoplasmic Reticulum Ca2+ handling and causes complex ventricular arrhythmias in mice. Cardiovasc Res. 2007; 75(1):69-78. PMC: 2717009. DOI: 10.1016/j.cardiores.2007.03.002. View

11.

Litwin S, Zhang D, Bridge J . Dyssynchronous Ca(2+) sparks in myocytes from infarcted hearts. Circ Res. 2000; 87(11):1040-7. DOI: 10.1161/01.res.87.11.1040. View

12.

Maclennan D, Wong P . Isolation of a calcium-sequestering protein from sarcoplasmic reticulum. Proc Natl Acad Sci U S A. 1971; 68(6):1231-5. PMC: 389160. DOI: 10.1073/pnas.68.6.1231. View

13.

Wang S, Song L, Lakatta E, Cheng H . Ca2+ signalling between single L-type Ca2+ channels and ryanodine receptors in heart cells. Nature. 2001; 410(6828):592-6. DOI: 10.1038/35069083. View

14.

Sobie E, Song L, Lederer W . Restitution of Ca(2+) release and vulnerability to arrhythmias. J Cardiovasc Electrophysiol. 2006; 17 Suppl 1:S64-S70. PMC: 1540408. DOI: 10.1111/j.1540-8167.2006.00385.x. View

15.

Takeshima H, Komazaki S, Nishi M, Iino M, Kangawa K . Junctophilins: a novel family of junctional membrane complex proteins. Mol Cell. 2000; 6(1):11-22. DOI: 10.1016/s1097-2765(00)00003-4. View

16.

Wu X, Bers D . Sarcoplasmic reticulum and nuclear envelope are one highly interconnected Ca2+ store throughout cardiac myocyte. Circ Res. 2006; 99(3):283-91. DOI: 10.1161/01.RES.0000233386.02708.72. View

17.

Knollmann B, Chopra N, Hlaing T, Akin B, Yang T, Ettensohn K . Casq2 deletion causes sarcoplasmic reticulum volume increase, premature Ca2+ release, and catecholaminergic polymorphic ventricular tachycardia. J Clin Invest. 2006; 116(9):2510-20. PMC: 1551934. DOI: 10.1172/JCI29128. View

18.

Gyorke I, Hester N, Jones L, Gyorke S . The role of calsequestrin, triadin, and junctin in conferring cardiac ryanodine receptor responsiveness to luminal calcium. Biophys J. 2004; 86(4):2121-8. PMC: 1304063. DOI: 10.1016/S0006-3495(04)74271-X. View

19.

Ogrodnik J, Niggli E . Increased Ca(2+) leak and spatiotemporal coherence of Ca(2+) release in cardiomyocytes during beta-adrenergic stimulation. J Physiol. 2009; 588(Pt 1):225-42. PMC: 2821561. DOI: 10.1113/jphysiol.2009.181800. View

20.

Gomez A, Valdivia H, Cheng H, Lederer M, Santana L, Cannell M . Defective excitation-contraction coupling in experimental cardiac hypertrophy and heart failure. Science. 1997; 276(5313):800-6. DOI: 10.1126/science.276.5313.800. View