Skip to main content
SpringerLink
Log in

Simulating cardiac Ca2+ release units: effects of RyR cluster size and Ca2+ buffers on diastolic Ca2+ leak

  • Original Article
  • Published:
Pflügers Archiv - European Journal of Physiology Aims and scope Submit manuscript

Abstract

Leak of Ca2+ out of the cardiac sarcoplasmic reticulum (SR) via ryanodine receptors (RyRs) during diastole is vital to regulate SR Ca2+ levels. This leak can become deleterious when large spontaneous RyR-mediated Ca2+ release events evoke proarrhythmic Ca2+ waves that can lead to delayed after-depolarizations. Here, we model diastolic SR Ca2+ leak at individual SR Ca2+ release sites using computer simulations of RyR arrays like those in the dyadic cleft. The results show that RyR arrays size has a significant effect on SR Ca2+ leak, with bigger arrays producing larger and more frequent Ca2+ release events. Moreover, big RyR arrays are more susceptible to small changes in the levels of dyadic Ca2+ buffers. Such changes in buffering shift Ca2+ leak from small Ca2+ release events (involving few open RyRs) to larger events (with many open RyRs). Moreover, by analyzing a large parameter space of possible buffering and SR Ca2+ loads, we find further evidence for the hypothesis that SR Ca2+ leak by RyR arrays can undergo a sudden phase transition.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Ai X, Curran JW, Shannon TR, Bers DM, Pogwizd SM (2005) Ca2+/calmodulin-dependent protein kinase modulates cardiac ryanodine receptor phosphorylation and sarcoplasmic reticulum Ca2+ leak in heart failure. Circ Res 97:1314–1322. https://doi.org/10.1161/01.RES.0000194329.41863.89

    Article  CAS  PubMed  Google Scholar 

  2. Barton G (1989) Elements of Green's functions and propagation: potentials, diffusion and waves. Oxford University Press, Oxford

    Google Scholar 

  3. Bers DM (2001) Excitation-contraction coupling and cardiac contractile force, 2nd edn. Kluwer Academic Publishers, Dordrecht

    Book  Google Scholar 

  4. Bers DM, Despa S (2006) Cardiac myocytes Ca2+ and Na+ regulation in normal and failing hearts. J Pharmacol Sci 100:315–322. https://doi.org/10.1254/jphs.CPJ06001X

    Article  CAS  PubMed  Google Scholar 

  5. Berti C, Zsolnay V, Shannon TR, Fill M, Gillespie D (2017) Sarcoplasmic reticulum Ca2+, Mg2+, K+, and Cl– concentrations adjust quickly as heart rate changes. J Mol Cell Cardiol 103:31–39

    Article  CAS  Google Scholar 

  6. Bovo E, Mazurek SR, Fill M, Zima AV (2015) Cytosolic Ca2+ buffering determines the intra-SR Ca2+ concentration at which cardiac Ca2+ sparks terminate. Cell Calcium 58:246–253. https://doi.org/10.1016/j.ceca.2015.06.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Cabra V, Murayama T, Samsó M (2016) Ultrastructural analysis of self-associated RyR2s. Biophys J 110:2651–2662. https://doi.org/10.1016/j.bpj.2016.05.013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Cannell MB, Kong CHT, Imtiaz MS, Laver DR (2013) 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. Biophys J 104:2149–2159. https://doi.org/10.1016/j.bpj.2013.03.058

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Cerrone M, Napolitano C, Priori SG (2009) Catecholaminergic polymorphic ventricular tachycardia: A paradigm to understand mechanisms of arrhythmias associated to impaired Ca2+ regulation. Heart Rhythm 6:1652–1659

    Article  Google Scholar 

  10. Chen H, Valle G, Furlan S, Nani A, Gyorke S, Fill M, Volpe P (2013) Mechanism of calsequestrin regulation of single cardiac ryanodine receptor in normal and pathological conditions. J Gen Physiol 142:127–136. https://doi.org/10.1085/jgp.201311022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Chen Y, Muratov CB, Matveev V (2020) Efficient approximations for stationary single-channel Ca2+ nanodomains across length scales. Biophys J 119:1239–1254. https://doi.org/10.1016/j.bpj.2020.06.038

    Article  CAS  PubMed  Google Scholar 

  12. Colquhoun D, Hawkes AG (1995) The principles of the stochastic interpretation of ion-channel mechanisms. In: Sakmann B, Neher E (eds) Single-Channel Recording, 2nd edn. Plenum Press, New York, pp 397–482

    Chapter  Google Scholar 

  13. Doenst T, Nguyen TD, Abel ED (2013) Cardiac metabolism in heart failure. Circ Res 113:709–724. https://doi.org/10.1161/CIRCRESAHA.113.300376

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Dyson FJ (1969) Existence of a phase-transition in a one-dimensional Ising ferromagnet. Commun Math Phys 12:91–107. https://doi.org/10.1007/bf01645907

    Article  Google Scholar 

  15. Dziarmaga J (2005) Dynamics of a quantum phase transition: Exact solution of the quantum Ising model. Phys Rev Lett 95:245701

    Article  Google Scholar 

  16. Fill M, Gillespie D (2018) Ryanodine receptor open times are determined in the closed state. Biophys J 115:1160–1165

    Article  CAS  Google Scholar 

  17. Galice S, Xie Y, Yang Y, Sato D, Bers DM (2018) Size matters: ryanodine receptor cluster size affects arrhythmogenic sarcoplasmic reticulum calcium release. J Am Heart Assoc 7:e008724. https://doi.org/10.1161/JAHA.118.008724

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Gillespie D (2020) Recruiting RyRs to open in a Ca2+ release unit: single-RyR gating properties make RyR group dynamics. Biophys J 118:232–242

    Article  CAS  Google Scholar 

  19. Gillespie D (2020) Simulating diffusion from a cluster of point sources using propagation integrals. Eur Biophys J 49:385–293. https://doi.org/10.1007/s00249-020-01438-9

    Article  CAS  PubMed  Google Scholar 

  20. Gillespie D, Fill M (2008) Intracellular calcium release channels mediate their own countercurrent: The ryanodine receptor case study. Biophys J 95:3706–3714

    Article  CAS  Google Scholar 

  21. Hou Y, Jayasinghe I, Crossman DJ, Baddeley D, Soeller C (2015) Nanoscale analysis of ryanodine receptor clusters in dyadic couplings of rat cardiac myocytes. J Mol Cell Cardiol 80:45–55. https://doi.org/10.1016/j.yjmcc.2014.12.013

    Article  CAS  PubMed  Google Scholar 

  22. Laver DR (2007) Ca2+ stores regulate ryanodine receptor Ca2+ release channels via luminal and cytosolic Ca2+ sites. Biophys J 92:3541–3555

    Article  CAS  Google Scholar 

  23. Laver DR, Honen BN (2008) Luminal Mg2+, a key factor controlling RYR2-mediated Ca2+ release: Cytoplasmic and luminal regulation modeled in a tetrameric channel. J Gen Physiol 132:429–446. https://doi.org/10.1085/jgp.200810001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Lee TD, Yang CN (1952) Statistical theory of equations of state and phase transitions II. Lattice gas and Ising model. Phys Rev 87:410–419

    Article  CAS  Google Scholar 

  25. Macquaide N, Tuan H-TM, Hotta J-i, Sempels W, Lenaerts I, Holemans P, Hofkens J, Jafri MS, Willems R, Sipido KR (2015) Ryanodine receptor cluster fragmentation and redistribution in persistent atrial fibrillation enhance calcium release. Cardiovasc Res 108:387–398. https://doi.org/10.1093/cvr/cvv231

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Maltsev AV, Maltsev VA, Stern MD (2017) Clusters of calcium release channels harness the Ising phase transition to confine their elementary intracellular signals. Proc Natl Acad Sci 114:7525–7530. https://doi.org/10.1073/pnas.1701409114

    Article  CAS  PubMed  Google Scholar 

  27. Maltsev AV, Stern MD, Maltsev VA (2019) Mechanisms of calcium leak from cardiac sarcoplasmic reticulum revealed by statistical mechanics. Biophys J 116:2212–2223. https://doi.org/10.1016/j.bpj.2019.04.031

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. McCoy BM, Wu TT (1973) The two-dimensional ising model. Harvard University Press, Cambridge

    Google Scholar 

  29. Neef S, Dybkova N, Sossalla S, Ort KR, Fluschnik N, Neumann K, Seipelt R, Schöndube FA, Hasenfuss G, Maier LS (2010) CaMKII-dependent diastolic SR Ca2+ leak and elevated diastolic Ca2+ levels in right atrial myocardium of patients with atrial fibrillation. Circ Res 106:1134–1144. https://doi.org/10.1161/CIRCRESAHA.109.203836

    Article  CAS  PubMed  Google Scholar 

  30. Neher E (1986) Concentration profiles of intracellular calcium in the presence of a diffusible chelator. In: Heinemann U, Klee M, Neher E (eds) Calcium Electrogenesis and Neuronal Functioning. Springer-Verlag, Berlin, pp 80–96

    Chapter  Google Scholar 

  31. Neher E (1998) Usefulness and limitations of linear approximations to the understanding of Ca++ signals. Cell Calcium 24:345–357. https://doi.org/10.1016/S0143-4160(98)90058-6

    Article  CAS  PubMed  Google Scholar 

  32. Priori SG, Chen SRW (2011) Inherited dysfunction of sarcoplasmic reticulum Ca2+ handling and arrhythmogenesis. Circ Res 108:871–883. https://doi.org/10.1161/circresaha.110.226845

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Rosca MG, Hoppel CL (2013) Mitochondrial dysfunction in heart failure. Heart Fail Rev 18:607–622. https://doi.org/10.1007/s10741-012-9340-0

    Article  CAS  PubMed  Google Scholar 

  34. Satoh H, Blatter LA, Bers DM (1997) Effects of [Ca2+]i, SR Ca2+ load, and rest on Ca2+ spark frequency in ventricular myocytes. Am J Phys Heart Circ Phys 272:H657–H668. https://doi.org/10.1152/ajpheart.1997.272.2.H657

    Article  CAS  Google Scholar 

  35. Shannon TR, Wang F, Puglisi J, Weber C, Bers DM (2004) A mathematical treatment of integrated Ca dynamics within the ventricular myocyte. Biophys J 87:3351–3371. https://doi.org/10.1529/biophysj.104.047449

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Shen X, van den Brink J, Hou Y, Colli D, Le C, Kolstad TR, MacQuaide N, Carlson CR, Kekenes-Huskey PM, Edwards AG, Soeller C, Louch WE (2019) 3D dSTORM imaging reveals novel detail of ryanodine receptor localization in rat cardiac myocytes. J Physiol 597:399–418. https://doi.org/10.1113/jp277360

    Article  CAS  PubMed  Google Scholar 

  37. Shigekawa M, Iwamoto T (2001) Cardiac Na+-Ca2+ Exchange: Molecular and pharmacological aspects. Circ Res 88:864–876. https://doi.org/10.1161/hh0901.090298

    Article  CAS  PubMed  Google Scholar 

  38. Stanley HE (1971) Introduction to Phase Transitions and Critical Phenomena. Oxford University Press, Oxford

    Google Scholar 

  39. Stern MD, Ríos E, Maltsev VA (2013) Life and death of a cardiac calcium spark. J Gen Physiol 142:257–274. https://doi.org/10.1085/jgp.201311034

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Vaughan-Jones RD, Spitzer KW, Swietach P (2009) Intracellular pH regulation in heart. J Mol Cell Cardiol 46:318–331. https://doi.org/10.1016/j.yjmcc.2008.10.024

    Article  CAS  PubMed  Google Scholar 

  41. Ventura-Clapier R, Garnier A, Veksler V (2004) Energy metabolism in heart failure. J Physiol 555:1–13. https://doi.org/10.1113/jphysiol.2003.055095

    Article  CAS  PubMed  Google Scholar 

  42. Wescott AP, Jafri MS, Lederer WJ, Williams GSB (2016) Ryanodine receptor sensitivity governs the stability and synchrony of local calcium release during cardiac excitation-contraction coupling. J Mol Cell Cardiol 92:82–92. https://doi.org/10.1016/j.yjmcc.2016.01.024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Xie Y, Yang Y, Galice S, Bers DM, Sato D (2019) Size matters: Ryanodine receptor cluster size heterogeneity potentiates calcium waves. Biophys J 116:530–539. https://doi.org/10.1016/j.bpj.2018.12.017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Yeomans JM (1992) Statistical mechanics of phase transitions. Oxford Univeristy Press, Oxford

    Google Scholar 

  45. Zhang YH, Hancox JC (2009) Regulation of cardiac Na+–Ca2+ exchanger activity by protein kinase phosphorylation—Still a paradox? Cell Calcium 45:1–10. https://doi.org/10.1016/j.ceca.2008.05.005

    Article  CAS  PubMed  Google Scholar 

  46. Zima AV, Picht E, Bers DM, Blatter LA (2008) Termination of cardiac Ca2+ sparks: role of intra-SR [Ca2+], release flux, and intra-SR Ca2+ diffusion. Circ Res 103:e105–e115. https://doi.org/10.1161/circresaha.107.183236

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Zima AV, Bovo E, Bers DM, Blatter LA (2010) Ca2+ spark-dependent and -independent sarcoplasmic reticulum Ca2+ leak in normal and failing rabbit ventricular myocytes. J Physiol 588:4743–4757. https://doi.org/10.1113/jphysiol.2010.197913

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Zsolnay V, Fill M, Gillespie D (2018) Sarcoplasmic reticulum Ca2+ release uses a cascading network of intra-SR and channel countercurrents. Biophys J 114:462–473

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Research reported in this publication was supported by National Heart, Lung, and Blood Institute of the National Institutes of Health under award number R01HL057832. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Author information

Authors and Affiliations

  1. Department of Physiology and Biophysics, Rush University Medical Center, Chicago, IL, USA

    Michael Fill & Dirk Gillespie

Authors
  1. Michael Fill
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dirk Gillespie
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dirk Gillespie.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the special issue on Calcium Signal Dynamics in Cardiac Myocytes and Fibroblasts: Mechanisms in Pflügers Archiv—European Journal of Physiology

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fill, M., Gillespie, D. Simulating cardiac Ca2+ release units: effects of RyR cluster size and Ca2+ buffers on diastolic Ca2+ leak. Pflugers Arch - Eur J Physiol 473, 435–446 (2021). https://doi.org/10.1007/s00424-021-02539-w

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00424-021-02539-w

Keywords

Search

Navigation