The ryanodine receptor store-sensing gate controls Ca2+ waves and Ca2+-triggered arrhythmias

Subjects

Abstract

Spontaneous Ca2+ release from intracellular stores is important for various physiological and pathological processes. In cardiac muscle cells, spontaneous store overload–induced Ca2+ release (SOICR) can result in Ca2+ waves, a major cause of ventricular tachyarrhythmias (VTs) and sudden death. The molecular mechanism underlying SOICR has been a mystery for decades. Here we show that a point mutation, E4872A, in the helix bundle crossing region (the proposed gate) of the cardiac ryanodine receptor (RyR2) completely abolishes luminal, but not cytosolic, Ca2+ activation of RyR2. The introduction of metal-binding histidines at this site converts RyR2 into a luminal Ni2+-gated channel. Mouse hearts harboring a heterozygous RyR2 mutation at this site (E4872Q) are resistant to SOICR and are completely protected against Ca2+-triggered VTs. These data show that the RyR2 gate directly senses luminal (store) Ca2+, explaining the regulation of RyR2 by luminal Ca2+, the initiation of Ca2+ waves and Ca2+-triggered arrhythmias. This newly identified store-sensing gate structure is conserved in all RyR and inositol 1,4,5-trisphosphate receptor isoforms.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: The E4872A mutation abolishes luminal, but not cytosolic, Ca2+ activation of RyR2.
Figure 2: Effects of E4872A and E4872Q on cytosolic Ca2+ activation of single RyR2 channels.
Figure 3: Mechanism of activation of RyR2 by luminal Ca2+.
Figure 4: Effect of E4872 mutations on SOICR.
Figure 5: Effect of the E4872Q RyR2 mutation on EC coupling.
Figure 6: Heterozygous E4872Q mutant mice are resistant to SOICR-induced VTs.

Accession codes

Accessions

Protein Data Bank

References

  1. 1

    Bers, D.M. Cardiac excitation-contraction coupling. Nature 415, 198–205 (2002).

    CAS  PubMed  Article  Google Scholar 

  2. 2

    Berridge, M.J., Bootman, M.D. & Roderick, H.L. Calcium signalling: dynamics, homeostasis and remodelling. Nat. Rev. Mol. Cell Biol. 4, 517–529 (2003).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  3. 3

    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. 85, 247–289 (1985).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  4. 4

    Bers, D.M. Calcium cycling and signaling in cardiac myocytes. Annu. Rev. Physiol. 70, 23–49 (2008).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  5. 5

    Irvine, R.F. 'Quantal' Ca2+ release and the control of Ca2+ entry by inositol phosphates—a possible mechanism. FEBS Lett. 263, 5–9 (1990).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  6. 6

    Missiaen, L., Taylor, C.W. & Berridge, M.J. Spontaneous calcium release from inositol trisphosphate-sensitive calcium stores. Nature 352, 241–244 (1991).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  7. 7

    Missiaen, L., Taylor, C.W. & Berridge, M.J. Luminal Ca2+ promoting spontaneous Ca2+ release from inositol trisphosphate-sensitive stores in rat hepatocytes. J. Physiol. (Lond.) 455, 623–640 (1992).

    CAS  PubMed Central  Article  Google Scholar 

  8. 8

    Nunn, D.L. & Taylor, C.W. Luminal Ca2+ increases the sensitivity of Ca2+ stores to inositol 1,4,5-trisphosphate. Mol. Pharmacol. 41, 115–119 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9

    Sitsapesan, R. & Williams, A. Regulation of the gating of the sheep cardiac sarcoplasmic reticulum Ca2+-release channel by luminal Ca2+. J. Membr. Biol. 137, 215–226 (1994).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  10. 10

    Bassani, J.W., Yuan, W., Bers, D.M. & Fractional, S.R. Ca release is regulated by trigger Ca and SR Ca content in cardiac myocytes. Am. J. Physiol. 268, C1313–C1319 (1995).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  11. 11

    Györke, I. & Gyorke, S. Regulation of the cardiac ryanodine receptor channel by luminal Ca2+ involves luminal Ca2+ sensing sites. Biophys. J. 75, 2801–2810 (1998).

    PubMed  PubMed Central  Article  Google Scholar 

  12. 12

    Xu, L. & Meissner, G. Regulation of cardiac muscle Ca2+ release channel by sarcoplasmic reticulum lumenal Ca2+. Biophys. J. 75, 2302–2312 (1998).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  13. 13

    Shannon, T.R., Ginsburg, K.S. & Bers, D.M. Potentiation of fractional sarcoplasmic reticulum calcium release by total and free intra-sarcoplasmic reticulum calcium concentration. Biophys. J. 78, 334–343 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  14. 14

    Jiang, D. et al. RyR2 mutations linked to ventricular tachycardia and sudden death reduce the threshold for store-overload–induced Ca2+ release (SOICR). Proc. Natl. Acad. Sci. USA 101, 13062–13067 (2004).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  15. 15

    Keller, M., Kao, J.P., Egger, M. & Niggli, E. Calcium waves driven by “sensitization” wave-fronts. Cardiovasc. Res. 74, 39–45 (2007).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  16. 16

    Kong, H. et al. Skeletal and cardiac ryanodine receptors exhibit different responses to Ca2+ overload and luminal Ca2+. Biophys. J. 92, 2757–2770 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  17. 17

    Györke, S. & Terentyev, D. Modulation of ryanodine receptor by luminal calcium and accessory proteins in health and cardiac disease. Cardiovasc. Res. 77, 245–255 (2008).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  18. 18

    Kass, R.S. & Tsien, R.W. Fluctuations in membrane current driven by intracellular calcium in cardiac Purkinje fibers. Biophys. J. 38, 259–269 (1982).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. 19

    Orchard, C.H., Eisner, D. & Allen, D. Oscillations of intracellular Ca2+ in mammalian cardiac muscle. Nature 304, 735–738 (1983).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  20. 20

    Stern, M.D., Kort, A., Bhatnagar, G. & Lakatta, E. Scattered-light intensity fluctuations in diastolic rat cardiac muscle caused by spontaneous Ca2+-dependent cellular mechanical oscillations. J. Gen. Physiol. 82, 119–153 (1983).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  21. 21

    Wier, W.G., Kort, A., Stern, M., Lakatta, E. & Marban, E. Cellular calcium fluctuations in mammalian heart: direct evidence from noise analysis of aequorin signals in Purkinje fibers. Proc. Natl. Acad. Sci. USA 80, 7367–7371 (1983).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  22. 22

    Marban, E., Robinson, S.W. & Wier, W.G. Mechanisms of arrhythmogenic delayed and early afterdepolarizations in ferret ventricular muscle. J. Clin. Invest. 78, 1185–1192 (1986).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. 23

    Schlotthauer, K. & Bers, D.M. Sarcoplasmic reticulum Ca2+ release causes myocyte depolarization. Underlying mechanism and threshold for triggered action potentials. Circ. Res. 87, 774–780 (2000).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  24. 24

    Bers, D.M. Calcium and cardiac rhythms: physiological and pathophysiological. Circ. Res. 90, 14–17 (2002).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  25. 25

    Pogwizd, S.M. & Bers, D.M. Cellular basis of triggered arrhythmias in heart failure. Trends Cardiovasc. Med. 14, 61–66 (2004).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  26. 26

    Jiang, D. et al. Enhanced store overload–induced Ca2+ release and channel sensitivity to luminal Ca2+ activation are common defects of RyR2 mutations linked to ventricular tachycardia and sudden death. Circ. Res. 97, 1173–1181 (2005).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  27. 27

    Priori, S.G. & Chen, S.R. Inherited dysfunction of sarcoplasmic reticulum Ca2+ handling and arrhythmogenesis. Circ. Res. 108, 871–883 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. 28

    Nelson, M.T. et al. Relaxation of arterial smooth muscle by calcium sparks. Science 270, 633–637 (1995).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  29. 29

    Lakatta, E.G., Maltsev, V.A. & Vinogradova, T.M. A coupled system of intracellular Ca2+ clocks and surface membrane voltage clocks controls the timekeeping mechanism of the heart's pacemaker. Circ. Res. 106, 659–673 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. 30

    Díaz, M.E., Trafford, A.W., O'Neill, S.C. & Eisner, D.A. Measurement of sarcoplasmic reticulum Ca2+ content and sarcolemmal Ca2+ fluxes in isolated rat ventricular myocytes during spontaneous Ca2+ release. J. Physiol. (Lond.) 501, 3–16 (1997).

    Article  Google Scholar 

  31. 31

    Eisner, D.A., Kashimura, T., Venetucci, L.A. & Trafford, A.W. From the ryanodine receptor to cardiac arrhythmias. Circ. J. 73, 1561–1567 (2009).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  32. 32

    Tripathy, A. & Meissner, G. Sarcoplasmic reticulum lumenal Ca2+ has access to cytosolic activation and inactivation sites of skeletal muscle Ca2+ release channel. Biophys. J. 70, 2600–2615 (1996).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. 33

    Jiang, D., Chen, W., Wang, R., Zhang, L. & Chen, S.R.W. Loss of luminal Ca2+ activation in the cardiac ryanodine receptor is associated with ventricular fibrillation and sudden death. Proc. Natl. Acad. Sci. USA 104, 18309–18314 (2007).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  34. 34

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  35. 35

    Liu, Y. et al. Flux regulation of cardiac ryanodine receptor channels. J. Gen. Physiol. 135, 15–27 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  36. 36

    Györke, I., Hester, N., Jones, L.R. & Gyorke, S. The role of calsequestrin, triadin, and junctin in conferring cardiac ryanodine receptor responsiveness to luminal calcium. Biophys. J. 86, 2121–2128 (2004).

    PubMed  PubMed Central  Article  Google Scholar 

  37. 37

    Knollmann, B.C. et al. Casq2 deletion causes sarcoplasmic reticulum volume increase, premature Ca2+ release, and catecholaminergic polymorphic ventricular tachycardia. J. Clin. Invest. 116, 2510–2520 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Sitsapesan, R. & Williams, A.J. Regulation of current flow through ryanodine receptors by luminal Ca2+. J. Membr. Biol. 159, 179–185 (1997).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  39. 39

    Kong, H. et al. Caffeine induces Ca2+ release by reducing the threshold for luminal Ca2+ activation of the ryanodine receptor. Biochem. J. 414, 441–452 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. 40

    Zhao, M. et al. Molecular identification of the ryanodine receptor pore-forming segment. J. Biol. Chem. 274, 25971–25974 (1999).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  41. 41

    Williams, A.J., West, D.J. & Sitsapesan, R. Light at the end of the Ca2+-release channel tunnel: structures and mechanisms involved in ion translocation in ryanodine receptor channels. Q. Rev. Biophys. 34, 61–104 (2001).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  42. 42

    Welch, W., Rheault, S., West, D.J. & Williams, A.J. A model of the putative pore region of the cardiac ryanodine receptor channel. Biophys. J. 87, 2335–2351 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. 43

    Xu, L., Wang, Y., Gillespie, D. & Meissner, G. Two rings of negative charges in the cytosolic vestibule of type-1 ryanodine receptor modulate ion fluxes. Biophys. J. 90, 443–453 (2006).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  44. 44

    Samsó, M., Feng, W., Pessah, I.N. & Allen, P.D. Coordinated movement of cytoplasmic and transmembrane domains of RyR1 upon gating. PLoS Biol. 7, e85 (2009).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  45. 45

    Doyle, D.A. et al. The structure of the potassium channel: molecular basis of K+ conduction and selectivity. Science 280, 69–77 (1998).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  46. 46

    Long, S.B., Campbell, E.B. & Mackinnon, R. Crystal structure of a mammalian voltage-dependent Shaker family K+ channel. Science 309, 897–903 (2005).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  47. 47

    Payandeh, J., Scheuer, T., Zheng, N. & Catterall, W.A. The crystal structure of a voltage-gated sodium channel. Nature 475, 353–358 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  48. 48

    Li, P. & Chen, S.R. Molecular basis of Ca2+ activation of the mouse cardiac Ca2+ release channel (ryanodine receptor). J. Gen. Physiol. 118, 33–44 (2001).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. 49

    Shi, N., Ye, S., Alam, A., Chen, L. & Jiang, Y. Atomic structure of a Na+- and K+-conducting channel. Nature 440, 570–574 (2006).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  50. 50

    Zhou, Q. et al. Carvedilol and its new analogs suppress arrhythmogenic store overload-induced Ca2+ release. Nat. Med. 17, 1003–1009 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  51. 51

    Liu, N. et al. Arrhythmogenesis in catecholaminergic polymorphic ventricular tachycardia: insights from a RyR2 R4496C knock-in mouse model. Circ. Res. 99, 292–298 (2006).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  52. 52

    Sedej, S. et al. Na+-dependent SR Ca2+ overload induces arrhythmogenic events in mouse cardiomyocytes with a human CPVT mutation. Cardiovasc. Res. 87, 50–59 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  53. 53

    Mitchell, R.D., Palade, P. & Fleischer, S. Spontaneous calcium release from sarcoplasmic reticulum. Assessment of other ionic influences. J. Biol. Chem. 259, 1073–1081 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    Fabiato, A. Two kinds of calcium-induced release of calcium from the sarcoplasmic reticulum of skinned cardiac cells. Adv. Exp. Med. Biol. 311, 245–262 (1992).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  55. 55

    Watanabe, H. et al. Flecainide prevents catecholaminergic polymorphic ventricular tachycardia in mice and humans. Nat. Med. 15, 380–383 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  56. 56

    Hilliard, F.A. et al. Flecainide inhibits arrhythmogenic Ca2+ waves by open state block of ryanodine receptor Ca2+ release channels and reduction of Ca2+ spark mass. J. Mol. Cell. Cardiol. 48, 293–301 (2010).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  57. 57

    Sitsapesan, R. & Williams, A. The gating of the sheep skeletal sarcoplasmic reticulum Ca2+-release channel is regulated by luminal Ca2+. J. Membr. Biol. 146, 133–144 (1995).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  58. 58

    Zhou, J., Launikonis, B.S., Rios, E. & Brum, G. Regulation of Ca2+ sparks by Ca2+ and Mg2+ in mammalian and amphibian muscle. An RyR isoform-specific role in excitation-contraction coupling? J. Gen. Physiol. 124, 409–428 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  59. 59

    Dabertrand, F., Mironneau, J., Macrez, N. & Morel, J.L. Full length ryanodine receptor subtype 3 encodes spontaneous calcium oscillations in native duodenal smooth muscle cells. Cell Calcium 44, 180–189 (2008).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  60. 60

    Ho, S.N., Hunt, H.D., Horton, R.M., Pullen, J.K. & Pease, L.R. Site-directed mutagenesis by overlap extension using the polymerase chain reaction. Gene 77, 51–59 (1989).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  61. 61

    Fabiato, A. & Fabiato, F. Calculator programs for computing the composition of the solutions containing multiple metals and ligands used for experiments in skinned muscle cells. J. Physiol. (Paris) 75, 463–505 (1979).

    CAS  Google Scholar 

  62. 62

    Jiang, D., Xiao, B., Zhang, L. & Chen, S.R. Enhanced basal activity of a cardiac Ca2+ release channel (ryanodine receptor) mutant associated with ventricular tachycardia and sudden death. Circ. Res. 91, 218–225 (2002).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  63. 63

    Hunt, D.J. et al. K201 (JTV519) suppresses spontaneous Ca2+ release and [3H]ryanodine binding to RyR2 irrespective of FKBP12.6 association. Biochem. J. 404, 431–438 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  64. 64

    Guatimosim, S., Guatimosim, C. & Song, L.S. Imaging calcium sparks in cardiac myocytes. Methods Mol. Biol. 689, 205–214 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  65. 65

    Wei, S. et al. T-tubule remodeling during transition from hypertrophy to heart failure. Circ. Res. 107, 520–531 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  66. 66

    Semeniuk, L.M., Kryski, A.J. & Severson, D.L. Echocardiographic assessment of cardiac function in diabetic db/db and transgenic db/db-hGLUT4 mice. Am. J. Physiol. Heart Circ. Physiol. 283, H976–H982 (2002).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  67. 67

    Laemmli, U.K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227, 680–65 (1970).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  68. 68

    Towbin, H., Staehelin, T. & Gordon, J. Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. Proc. Natl. Acad. Sci. USA 76, 4350–434 (1979).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  69. 69

    Thompson, J.D., Higgins, D.G. & Gibson, T.J. CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res. 22, 4673–4680 (1994).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  70. 70

    Jiang, Y. et al. Crystal structure and mechanism of a calcium-gated potassium channel. Nature 417, 515–522 (2002).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  71. 71

    Schwede, T., Kopp, J., Guex, N. & Peitsch, M.C. SWISS-MODEL: an automated protein homology-modeling server. Nucleic Acids Res. 31, 3381–3385 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  72. 72

    Guex, N. & Peitsch, M.C. SWISS-MODEL and the Swiss-PdbViewer: an environment for comparative protein modeling. Electrophoresis 18, 2714–2723 (1997).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  73. 73

    Baker, N.A., Sept, D., Joseph, S., Holst, M.J. & McCammon, J.A. Electrostatics of nanosystems: application to microtubules and the ribosome. Proc. Natl. Acad. Sci. USA 98, 10037–10041 (2001).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  74. 74

    Humphrey, W., Dalke, A. & Schulten, K. VMD: visual molecular dynamics. J. Mol. Graph. 14, 33–38 (1996).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by research grants from the Canadian Institutes of Health Research (CIHR) to H.J.D., D.P.T. and S.R.W.C., the US National Institutes of Health to J.C., L.-S.S., M.F. and S.R.W.C., the Heart and Stroke Foundation of Alberta to A.M.G., H.J.D. and S.R.W.C. and the Canada Foundation for Innovation (S.R.W.C.) and by the Heart and Stroke Foundation/Libin Cardiovascular Institute Professorship in Cardiovascular Research (S.R.W.C.). We are grateful for generous donations from the King family, the Howarth family and the Libin Cardiovascular Institute of Alberta. We are also grateful to W.C. Claycomb from the Louisiana State University Health Sciences Center for kindly providing the HL-1 cardiac cell line and to J. Lytton from the University of Calgary for the gift of the β-actin–specific antibody. W.C., X.Z. and X.T. are recipients of the Alberta Innovates-Health Solutions (AIHS) Studentship Award; P.P.J. is a recipient of AIHS and Heart and Stroke Foundation Fellowship Awards; M.L.O. is the recipient of a CIHR Fellowship Award; and H.J.D., D.P.T. and S.R.W.C. are recipients of AIHS Scientist Awards.

Author information

Affiliations

Authors

Contributions

W.C., R.W., B.C., X.Z., H.K., Y.B., Q.Z., A.G., X.T., P.P.J., M.L.O., J.C., D.P.T., A.M.G., H.J.D., M.F., L.-S.S. and S.R.W.C. designed research. W.C., R.W., B.C., X.Z., H.K., Y.B., Q.Z., C.X., Jingqun Zhang, A.G., X.T., P.P.J., M.L.O., Y.L., T.M., L.Z., J.B., L.S., H.C. and Jianlin Zhang performed research. W.C., R.W., Y.B., X.Z., H.K., Y.B., Q.Z., C.X., Jingqun Zhang, A.G., X.T., P.P.J., M.L.O., Y.L., T.M., L.Z., J.B., Jianlin Zhang, L.-S.S. and S.R.W.C. analyzed data. W.C., X.Z., Y.B., P.P.J., M.L.O., M.F., L.-S.S. and S.R.W.C. wrote the paper.

Corresponding author

Correspondence to S R Wayne Chen.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–8 and Supplementary Table 1. (PDF 6586 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Chen, W., Wang, R., Chen, B. et al. The ryanodine receptor store-sensing gate controls Ca2+ waves and Ca2+-triggered arrhythmias. Nat Med 20, 184–192 (2014). https://doi.org/10.1038/nm.3440

Download citation

Further reading

Search

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing