Structural Details of the Ryanodine Receptor Calcium Release Channel and Its Gating Mechanism

Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 981)

Abstract

Ryanodine receptors (RyRs) are large intracellular calcium release channels that play a crucial role in coupling excitation to contraction in both cardiac and skeletal muscle cells. In addition, they are expressed in other cell types where their function is less well understood. Hundreds of mutations in the different isoforms of RyR have been associated with inherited myopathies and cardiac arrhythmia disorders. The structure of these important drug targets remained elusive for a long time, despite decades of intensive research. In the recent years, a technical revolution in the field of single particle cryogenic electron microscopy (SP cryo-EM) allowed solving high-resolution structures of the skeletal and cardiac RyR isoforms. Together with the structures of individual domains solved by X-ray crystallography, this resulted in an unprecedented understanding of the structure, gating and regulation of these largest known ion channels. In this chapter we describe the recently solved high-resolution structures of RyRs, discuss molecular details of the channel gating, regulation and the disease mutations. Additionally, we highlight important questions that require further progress in structural studies of RyRs.

Keywords

Calcium signalling Ryanodine receptor Ion channel gating Cryo-EM 

Notes

Acknowledgements

This work was funded by grants from VIB, FWO grant number G.0266.15N and IWT fellowship number 131261 to K.W.

References

  1. 1.
    Rebbeck RT, Karunasekara Y, Board PG et al (2014) Skeletal muscle excitation–contraction coupling: who are the dancing partners? Int J Biochem Cell Biol 48:28–38. https://doi.org/10.1016/j.biocel.2013.12.001CrossRefPubMedGoogle Scholar
  2. 2.
    Lanner JT, Georgiou DK, Joshi AD, Hamilton SL (2010) Ryanodine receptors: structure, expression, molecular details, and function in calcium release. Cold Spring Harb Perspect Biol 2:a003996CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Rogers EF, Koniuszy FR (1948) Plant insecticides; ryanodine, a new alkaloid from Ryania speciosa Vahl. J Am Chem Soc 70:3086–3088CrossRefPubMedGoogle Scholar
  4. 4.
    Fleischer S, Ogunbunmi EM, Dixon MC, Fleer EA (1985) Localization of Ca2+ release channels with ryanodine in junctional terminal cisternae of sarcoplasmic reticulum of fast skeletal muscle. Proc Natl Acad Sci USA 82:7256–7259CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Imagawa T, Smith JS, Coronado R, Campbell KP (1987) Purified ryanodine receptor from skeletal muscle sarcoplasmic reticulum is the Ca2+-permeable pore of the calcium release channel. J Biol Chem 262:16636–16643PubMedGoogle Scholar
  6. 6.
    Lai FA, Erickson HP, Rousseau E et al (1988b) Purification and reconstitution of the calcium release channel from skeletal muscle. Nature 331:315–319CrossRefPubMedGoogle Scholar
  7. 7.
    Pessah IN, Francini AO, Scales DJ et al (1986) Calcium-ryanodine receptor complex. Solubilization and partial characterization from skeletal muscle junctional sarcoplasmic reticulum vesicles. J Biol Chem 261:8643–8648PubMedGoogle Scholar
  8. 8.
    Franzini-Armstrong C (1970) Studies of the triad: I. Structure of the junction in frog twitch fibers. J Cell Biol 47:488–499CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Lai FA, Anderson K, Rousseau E et al (1988a) Evidence for a Ca2+ channel within the ryanodine receptor complex from cardiac sarcoplasmic reticulum. Biochem Biophys Res Commun 151:441–449CrossRefPubMedGoogle Scholar
  10. 10.
    Chen SR, Leong P, Imredy JP et al (1997a) Single-channel properties of the recombinant skeletal muscle Ca2+ release channel (ryanodine receptor). Biophys J 73:1904–1912CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Chen SRW, Li X, Ebisawa K, Zhang L (1997b) Functional characterization of the recombinant type 3 Ca2+ release channel (ryanodine receptor) expressed in HEK293 cells. J Biol Chem 272:24234–24246CrossRefPubMedGoogle Scholar
  12. 12.
    Li P, Chen SR (2001) Molecular basis of Ca(2)+ activation of the mouse cardiac Ca(2)+ release channel (ryanodine receptor). J Gen Physiol 118:33–44CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Lanner JT (2012) Ryanodine receptor physiology and its role in disease. In: Calcium signaling. Springer, Netherlands, p 217–234Google Scholar
  14. 14.
    Yuchi Z, Van Petegem F (2016) Ryanodine receptors under the magnifying lens: insights and limitations of cryo-electron microscopy and X-ray crystallography studies. Cell Calcium 59:209–227CrossRefPubMedGoogle Scholar
  15. 15.
    Conti A, Gorza L, Sorrentino V (1996) Differential distribution of ryanodine receptor type 3 (RyR3) gene product in mammalian skeletal muscles. Biochem J 316(Pt 1):19–23CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Giannini G, Conti A, Mammarella S et al (1995) The ryanodine receptor/calcium channel genes are widely and differentially expressed in murine brain and peripheral tissues. J Cell Biol 128:893–904CrossRefPubMedGoogle Scholar
  17. 17.
    Ottini L, Marziali G, Conti A et al (1996) Alpha and beta isoforms of ryanodine receptor from chicken skeletal muscle are the homologues of mammalian RyR1 and RyR3. Biochem J 315:207–216CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Oyamada H, Murayama T, Takagi T et al (1994) Primary structure and distribution of ryanodine-binding protein isoforms of the bullfrog skeletal muscle. J Biol Chem 269:17206–17214PubMedGoogle Scholar
  19. 19.
    Takeshima H, Nishi M, Iwabe N et al (1994) Isolation and characterization of a gene for a ryanodine receptor/calcium release channel in Drosophila melanogaster. FEBS Lett 337:81–87CrossRefPubMedGoogle Scholar
  20. 20.
    Sattelle DB, Cordova D, Cheek TR (2008) Insect ryanodine receptors: molecular targets for novel pest control chemicals. Invert Neurosci 8:107–119CrossRefPubMedGoogle Scholar
  21. 21.
    Franzini-Armstrong C, Protasi F, Ramesh V (1999) Shape, size, and distribution of Ca(2+) release units and couplons in skeletal and cardiac muscles. Biophys J 77:1528–1539CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Yin CC, Lai FA (2000) Intrinsic lattice formation by the ryanodine receptor calcium-release channel. Nat Cell Biol 2:669–671CrossRefPubMedGoogle Scholar
  23. 23.
    Franzini-Armstrong C, Nunzi G (1983) Junctional feet and particles in the triads of a fast-twitch muscle fibre. J Muscle Res Cell Motil 4:233–252CrossRefPubMedGoogle Scholar
  24. 24.
    Marx SO, Gaburjakova J, Gaburjakova M et al (2001) Coupled gating between cardiac calcium release channels (ryanodine receptors). Circ Res 88:1151–1158CrossRefPubMedGoogle Scholar
  25. 25.
    Marx SO, Ondrias K, Marks AR (1998) Coupled gating between individual skeletal muscle Ca2+ release channels (ryanodine receptors). Science 281:818–821CrossRefPubMedGoogle Scholar
  26. 26.
    Evans AM, Fameli N, Ogunbayo OA et al (2016) From contraction to gene expression: nanojunctions of the sarco/endoplasmic reticulum deliver site- and function-specific calcium signals. Sci China Life Sci 59:749–763CrossRefPubMedGoogle Scholar
  27. 27.
    van Breemen C, Fameli N, Evans AM (2013) Pan-junctional sarcoplasmic reticulum in vascular smooth muscle: nanospace Ca2+ transport for site- and function-specific Ca2+ signalling. J Physiol 591:2043–2054CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Boittin F-X, Galione A, Evans AM (2002) Nicotinic acid adenine dinucleotide phosphate mediates Ca2+ signals and contraction in arterial smooth muscle via a two-pool mechanism. Circ Res 91:1168–1175CrossRefPubMedGoogle Scholar
  29. 29.
    Marius P, Guerra MT, Nathanson MH et al (2006) Calcium release from ryanodine receptors in the nucleoplasmic reticulum. Cell Calcium 39:65–73CrossRefPubMedGoogle Scholar
  30. 30.
    Betzenhauser MJ, Marks AR (2010) Ryanodine receptor channelopathies. Pflugers Arch – Eur J Physiol 460:467–480CrossRefGoogle Scholar
  31. 31.
    Stenson PD, Mort M, Ball EV et al (2017) The human gene mutation database: towards a comprehensive repository of inherited mutation data for medical research, genetic diagnosis and next-generation sequencing studies. Hum Genet 526:68–13Google Scholar
  32. 32.
    Abdul M, Ramlal S, Hoosein N (2008) Ryanodine receptor expression correlates with tumor grade in breast cancer. Pathol Oncol Res 14:157–160CrossRefPubMedGoogle Scholar
  33. 33.
    Zhang L, Liu Y, Song F et al (2011) Functional SNP in the microRNA-367 binding site in the 3'UTR of the calcium channel ryanodine receptor gene 3 (RYR3) affects breast cancer risk and calcification. Proc Natl Acad Sci USA 108:13653–13658CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Lau K, Van Petegem F (2014) Crystal structures of wild type and disease mutant forms of the ryanodine receptor SPRY2 domain. Nat Comms 5:5397CrossRefGoogle Scholar
  35. 35.
    Sharma P, Ishiyama N, Nair U et al (2012) Structural determination of the phosphorylation domain of the ryanodine receptor. FEBS J 279:3952–3964CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Tung C-C, Lobo PA, Kimlicka L, Van Petegem F (2010) The amino-terminal disease hotspot of ryanodine receptors forms a cytoplasmic vestibule. Nature 468:585–588CrossRefPubMedGoogle Scholar
  37. 37.
    Yuchi Z, Lau K, Van Petegem F (2012) Disease mutations in the ryanodine receptor central region: crystal structures of a phosphorylation hot spot domain. Structure 20:1201–1211CrossRefPubMedGoogle Scholar
  38. 38.
    Yuchi Z, Yuen SMWK, Lau K et al (2015) Crystal structures of ryanodine receptor SPRY1 and tandem-repeat domains reveal a critical FKBP12 binding determinant. Nat Commun 6:1–13CrossRefGoogle Scholar
  39. 39.
    Kühlbrandt W (2014) Cryo-EM enters a new era. eLife 3:e03678CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    des Georges A, Clarke OB, Zalk R et al (2016) Structural basis for gating and activation of RyR1. Cell 167:145–157.e17CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Yan Z, Bai X-C, Yan C et al (2015) Structure of the rabbit ryanodine receptor RyR1 at near-atomic resolution. Nature 517:50–55CrossRefPubMedGoogle Scholar
  42. 42.
    Bonilla E (1977) Staining of transverse tubular system of skeletal muscle by tannic acid-glutaraldehyde fixation. J Ultrastruct Res 2:162–165CrossRefGoogle Scholar
  43. 43.
    Revel JP (1962) The sarcoplasmic reticulum of the bat cricothroid muscle. J Cell Biol 12:571–588CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Wagenknecht T, Grassucci R, Frank J et al (1989) Three-dimensional architecture of the calcium channel/foot structure of sarcoplasmic reticulum. Nature 338:167–170CrossRefPubMedGoogle Scholar
  45. 45.
    Bai X-C, Yan Z, Wu J et al (2016) The central domain of RyR1 is the transducer for long-range allosteric gating of channel opening. Cell Res 26:995–1006CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Efremov RG, Leitner A, Aebersold R, Raunser S (2015) Architecture and conformational switch mechanism of the ryanodine receptor. Nature 517:39–43CrossRefPubMedGoogle Scholar
  47. 47.
    Peng W, Shen H, Wu J et al (2016) Structural basis for the gating mechanism of the type 2 ryanodine receptor RyR2. Science 354:1–17Google Scholar
  48. 48.
    Zalk R, Clarke OB, des Georges A et al (2015) Structure of a mammalian ryanodine receptor. Nature 517:44–49CrossRefPubMedGoogle Scholar
  49. 49.
    Serysheva II, Schatz M, van Heel M et al (1999) Structure of the skeletal muscle calcium release channel activated with Ca2+ and AMP-PCP. Biophys J 77:1936–1944CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Seo M-D, Velamakanni S, Ishiyama N et al (2012) Structural and functional conservation of key domains in InsP3 and ryanodine receptors. Nature 483:108–112CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Ponting C, Schultz J, Bork P (1997) SPRY domains in ryanodine receptors (Ca(2+)-release channels). Trends Biochem Sci 22:193–194CrossRefPubMedGoogle Scholar
  52. 52.
    Wang D, Li Z, Messing EM, Wu G (2002) Activation of Ras/Erk pathway by a novel MET-interacting protein RanBPM. J Biol Chem 277:36216–36222CrossRefPubMedGoogle Scholar
  53. 53.
    Perez CF, Mukherjee S, Allen PD (2011) Amino acids 1-1,680 of ryanodine receptor type 1 hold critical determinants of skeletal type for excitation-contraction coupling: role of divergence domain D2. J Biol Chem 278:39644–39652CrossRefGoogle Scholar
  54. 54.
    Sorrentino V, Volpe P (1993) Ryanodine receptors: how many, where and why? Trends Pharmacol Sci 14:98–103CrossRefPubMedGoogle Scholar
  55. 55.
    Zorzato F, Fujii J, Otsu K et al (1990) Molecular cloning of cDNA encoding human and rabbit forms of the Ca2+ release channel (ryanodine receptor) of skeletal muscle sarcoplasmic reticulum. J Biol Chem 265:2244–2256PubMedGoogle Scholar
  56. 56.
    Cabra V, Murayama T, Samsó M (2016) Ultrastructural analysis of self-associated RyR2s. Biophys J 110:2651–2662CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Marcotte EM, Pellegrini M, Yeates TO, Eisenberg D (1999) A census of protein repeats. J Mol Biol 293:151–160CrossRefPubMedGoogle Scholar
  58. 58.
    Coates JC (2003) Armadillo repeat proteins: beyond the animal kingdom. Trends Cell Biol 13:463–471CrossRefPubMedGoogle Scholar
  59. 59.
    Zhang H, Zhang J-Z, Danila CI, Hamilton SL (2003) A noncontiguous, intersubunit binding site for calmodulin on the skeletal muscle Ca2+ release channel. J Biol Chem 278:8348–8355CrossRefPubMedGoogle Scholar
  60. 60.
    Smart OS, Neduvelil JG, Wang X et al (1996) HOLE: a program for the analysis of the pore dimensions of ion channel structural models. J Mol Graph 14:354–360CrossRefPubMedGoogle Scholar
  61. 61.
    Du GG, Khanna VK, MacLennan DH (2000) Mutation of divergent region 1 alters caffeine and Ca(2+) sensitivity of the skeletal muscle Ca(2+) release channel (ryanodine receptor). J Biol Chem 275:11778–11783CrossRefPubMedGoogle Scholar
  62. 62.
    Tompa P, Schad E, Tantos A, Kalmar L (2015) Intrinsically disordered proteins: emerging interaction specialists. Curr Opin Struct Biol 35:49–59CrossRefPubMedGoogle Scholar
  63. 63.
    Guo W, Sun B, Xiao Z et al (2016) The EF-hand Ca2+ binding domain is not required for cytosolic Ca2+ activation of the cardiac ryanodine receptor. J Biol Chem 291:2150–2160CrossRefPubMedGoogle Scholar
  64. 64.
    Euden J, Mason SA, Viero C et al (2013) Investigations of the contribution of a putative glycine hinge to ryanodine receptor channel gating. J Biol Chem 288:16671–16679CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Mei Y, Xu L, Mowrey DD et al (2015) Channel gating dependence on pore lining helix glycine residues in skeletal muscle ryanodine receptor. J Biol Chem 290:17535–17545CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Chen SR, Ebisawa K, Li X, Zhang L (1998) Molecular identification of the ryanodine receptor Ca2+ sensor. J Biol Chem 273:14675–14678CrossRefPubMedGoogle Scholar
  67. 67.
    Miyakawa T, Mizushima A, Hirose K et al (2001) Ca(2+)-sensor region of IP(3) receptor controls intracellular Ca(2+) signaling. The EMBO J 20:1674–1680CrossRefPubMedGoogle Scholar
  68. 68.
    Uchida K, Miyauchi H, Furuichi T et al (2003) Critical regions for activation gating of the inositol 1,4,5-trisphosphate receptor. J Biol Chem 278:16551–16560CrossRefPubMedGoogle Scholar
  69. 69.
    Kong H, Jones PP, Koop A et al (2008) Caffeine induces Ca2+ release by reducing the threshold for luminal Ca2+ activation of the ryanodine receptor. Biochem J 414:441–452CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Chan WM, Welch W, Sitsapesan R (2000) Structural factors that determine the ability of adenosine and related compounds to activate the cardiac ryanodine receptor. Br J Pharmacol 130:1618–1626CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Kermode H, Williams AJ, Sitsapesan R (1998) The interactions of ATP, ADP, and inorganic phosphate with the sheep cardiac ryanodine receptor. Biophys J 74:1296–1304CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    MacIntosh BR, Holash RJ, Renaud JM (2012) Skeletal muscle fatigue – regulation of excitation-contraction coupling to avoid metabolic catastrophe. J Cell Sci 125:2105–2114CrossRefPubMedGoogle Scholar
  73. 73.
    Smith JS, Coronado R, Meissner G (1985) Sarcoplasmic reticulum contains adenine nucleotide-activated calcium channels. Nature 316:446–449CrossRefPubMedGoogle Scholar
  74. 74.
    Mukherjee S, Thomas NL, Williams AJ (2014) Insights into the gating mechanism of the ryanodine-modified human cardiac Ca2+-release channel (ryanodine receptor 2). Mol Pharmacol 86:318–329CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Bhat MB, Zhao J, Takeshima H, Ma J (1997) Functional calcium release channel formed by the carboxyl-terminal portion of ryanodine receptor. Biophys J 73:1329–1336CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Callaway C, Seryshev A, Wang JP et al (1994) Localization of the high and low affinity [3H]ryanodine binding sites on the skeletal muscle Ca2+ release channel. J Biol Chem 269:15876–15884PubMedGoogle Scholar
  77. 77.
    Witcher DR, McPherson PS, Kahl SD et al (1994) Photoaffinity labeling of the ryanodine receptor/Ca2+ release channel with an azido derivative of ryanodine. J Biol Chem 269:13076–13079PubMedGoogle Scholar
  78. 78.
    Ranatunga KM, Moreno-King TM, Tanna B et al (2005) The Gln4863Ala mutation within a putative, pore-lining trans-membrane helix of the cardiac ryanodine receptor channel alters both the kinetics of ryanoid interaction and the subsequent fractional conductance. Mol Pharmacol 68:840–846PubMedGoogle Scholar
  79. 79.
    Wang R, Zhang L, Bolstad J et al (2003) Residue Gln4863 within a predicted transmembrane sequence of the Ca2+ release channel (ryanodine receptor) is critical for ryanodine interaction. J Biol Chem 278:51557–51565CrossRefPubMedGoogle Scholar
  80. 80.
    Tanna B, Welch W, Ruest L et al (2003) An anionic ryanoid, 10-O-succinoylryanodol, provides insights into the mechanisms governing the interaction of ryanoids and the subsequent altered function of ryanodine-receptor channels. J Gen Physiol 121:551–561CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Wei R, Wang X, Zhang Y et al (2016) Structural insights into Ca(2+)-activated long-range allosteric channel gating of RyR1. Cell Res 26:977–994CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Wong PW, Brackney WR, Pessah IN (1997) Ortho-substituted polychlorinated biphenyls alter microsomal calcium transport by direct interaction with ryanodine receptors of mammalian brain. J Biol Chem 272:15145–15153CrossRefPubMedGoogle Scholar
  83. 83.
    Wong PW, Pessah IN (1997) Noncoplanar PCB 95 alters microsomal calcium transport by an immunophilin FKBP12-dependent mechanism. Mol Pharmacol 51:693–702CrossRefPubMedGoogle Scholar
  84. 84.
    Walweel K, Li J, Molenaar P et al (2014) Differences in the regulation of RyR2 from human, sheep, and rat by Ca2+ and Mg2+ in the cytoplasm and in the lumen of the sarcoplasmic reticulum. J Gen Physiol 144:263–271CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Clarke OB, Hendrickson WA (2016) Structures of the colossal RyR1 calcium release channel. Curr Opin Struct Biol 39:144–152CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Brillantes AB, Ondrias K, Scott A et al (1994) Stabilization of calcium release channel (ryanodine receptor) function by FK506-binding protein. Cell 77:513–523CrossRefPubMedGoogle Scholar
  87. 87.
    Gaburjakova M, Gaburjakova J, Reiken S et al (2001) FKBP12 binding modulates ryanodine receptor channel gating. J Biol Chem 276:16931–16935CrossRefPubMedGoogle Scholar
  88. 88.
    Xiao J, Tian X, Jones PP et al (2007) Removal of FKBP12.6 does not alter the conductance and activation of the cardiac ryanodine receptor or the susceptibility to stress-induced ventricular arrhythmias. J Biol Chem 282:34828–34838CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    Buratti R, Prestipino G, Menegazzi P et al (1995) Calcium dependent activation of skeletal muscle Ca2+ release channel (ryanodine receptor) by calmodulin. Biochem Biophys Res Commun 213:1082–1090CrossRefPubMedGoogle Scholar
  90. 90.
    Balshaw DM, Xu L, Yamaguchi N et al (2001) Calmodulin binding and inhibition of cardiac muscle calcium release channel (ryanodine receptor). J Biol Chem 276:20144–20153CrossRefPubMedGoogle Scholar
  91. 91.
    Huang X, Fruen B, Farrington DT et al (2012) Calmodulin-binding locations on the skeletal and cardiac ryanodine receptors. J Biol Chem 287:30328–30335CrossRefPubMedPubMedCentralGoogle Scholar
  92. 92.
    Samsó M, Wagenknecht T (2002) Apocalmodulin and Ca2+-calmodulin bind to neighboring locations on the ryanodine receptor. J Biol Chem 277:1349–1353. https://doi.org/10.1074/jbc.M109196200CrossRefPubMedGoogle Scholar
  93. 93.
    Maximciuc AA, Putkey JA, Shamoo Y, Mackenzie KR (2006) Complex of calmodulin with a ryanodine receptor target reveals a novel, flexible binding mode. Structure 14:1547–1556CrossRefPubMedGoogle Scholar
  94. 94.
    Xiong L, Zhang J-Z, He R, Hamilton SL (2006) A Ca2+-binding domain in RyR1 that interacts with the calmodulin binding site and modulates channel activity. Biophys J 90:173–182CrossRefPubMedGoogle Scholar
  95. 95.
    Dobrev D, Wehrens XHT (2014) Role of RyR2 phosphorylation in heart failure and arrhythmias: controversies around ryanodine receptor phosphorylation in cardiac disease. Circ Res 114:1311–1319CrossRefPubMedPubMedCentralGoogle Scholar
  96. 96.
    Durham WJ, Aracena-Parks P, Long C et al (2008) RyR1 S-nitrosylation underlies environmental heat stroke and sudden death in Y522S RyR1 knockin mice. Cell 133:53–65CrossRefPubMedPubMedCentralGoogle Scholar
  97. 97.
    Marx SO, Reiken S, Hisamatsu Y et al (2000) PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (ryanodine receptor): defective regulation in failing hearts. Cell 101:365–376CrossRefPubMedGoogle Scholar
  98. 98.
    Aracena P, Tang W, Hamilton SL, Cecilia Hidalgo PD (2013) Effects of S-glutathionylation and S-nitrosylation on calmodulin binding to triads and FKBP12 binding to type 1 calcium release channels. Antioxid Redox Signal 7:870–881CrossRefGoogle Scholar
  99. 99.
    Benkusky NA, Farrell EF, Valdivia HH (2004) Ryanodine receptor channelopathies. Biochem Biophys Res Commun 322:1280–1285CrossRefPubMedGoogle Scholar
  100. 100.
    Del Prete D, Checler F, Chami M (2014) Ryanodine receptors: physiological function and deregulation in Alzheimer disease. Mol Neurodegener 9:21CrossRefPubMedPubMedCentralGoogle Scholar
  101. 101.
    Raymond LA (2017) Striatal synaptic dysfunction and altered calcium regulation in Huntington disease. Biochem Biophys Res Commun 483:1051–1062. https://doi.org/10.1016/j.bbrc.2016.07.058CrossRefPubMedGoogle Scholar
  102. 102.
    Bellinger AM, Reiken S, Carlson C et al (2009) Hypernitrosylated ryanodine receptor calcium release channels are leaky in dystrophic muscle. Nat Med 15:325–330CrossRefPubMedPubMedCentralGoogle Scholar
  103. 103.
    Lehnart SE, Mongillo M, Bellinger A et al (2008) Leaky Ca2+ release channel/ryanodine receptor 2 causes seizures and sudden cardiac death in mice. J Clin Invest 118:2230–2245PubMedPubMedCentralGoogle Scholar
  104. 104.
    Avila G, O’Brien JJ, Dirksen RT (2001) Excitation–contraction uncoupling by a human central core disease mutation in the ryanodine receptor. Proc Natl Acad Sci USA 98:4215–4220CrossRefPubMedPubMedCentralGoogle Scholar
  105. 105.
    Avila G, Dirksen RT (2001) Functional effects of central core disease mutations in the cytoplasmic region of the skeletal muscle ryanodine receptor. J Gen Physiol 118:277–290CrossRefPubMedPubMedCentralGoogle Scholar
  106. 106.
    George CH, Higgs GV, Lai FA (2003) Ryanodine receptor mutations associated with stress-induced ventricular tachycardia mediate increased calcium release in stimulated cardiomyocytes. Circ Res 93:531–540CrossRefPubMedGoogle Scholar
  107. 107.
    Jiang D, Xiao B, Zhang L, Chen SRW (2002) Enhanced basal activity of a cardiac Ca2+ release channel (ryanodine receptor) mutant associated with ventricular tachycardia and sudden death. Circ Res 91:218–225CrossRefPubMedGoogle Scholar
  108. 108.
    Jones PP, Jiang D, Bolstad J et al (2008) Endoplasmic reticulum Ca2+ measurements reveal that the cardiac ryanodine receptor mutations linked to cardiac arrhythmia and sudden death alter the threshold for store-overload-induced Ca2+ release. Biochem J 412:171CrossRefPubMedGoogle Scholar
  109. 109.
    Tang Y, Tian X, Wang R et al (2012) Abnormal termination of Ca2+ release is a common defect of RyR2 mutations associated with cardiomyopathies. Circ Res 110:968–977CrossRefPubMedPubMedCentralGoogle Scholar
  110. 110.
    Tiso N, Stephan DA, Nava A et al (2001) Identification of mutations in the cardiac ryanodine receptor gene in families affected with arrhythmogenic right ventricular cardiomyopathy type 2 (ARVD2). Hum Mol Genet 10:189–194CrossRefPubMedGoogle Scholar
  111. 111.
    Xiao Z, Guo W, Sun B et al (2016) Enhanced cytosolic Ca2+ activation underlies a common defect of central domain cardiac ryanodine receptor mutations linked to arrhythmias. J Biol Chem 291:24528–24537CrossRefPubMedPubMedCentralGoogle Scholar
  112. 112.
    Jiang D, Chen W, Wang R et al (2007) Loss of luminal Ca2+ activation in the cardiac ryanodine receptor is associated with ventricular fibrillation and sudden death. Proc Natl Acad Sci USA 104:18309–18314CrossRefPubMedPubMedCentralGoogle Scholar
  113. 113.
    Gonsalves SG, Ng D, Johnston JJ et al (2013) Using exome data to identify malignant hyperthermia susceptibility mutations. Anesthesiology 119:1043–1053CrossRefPubMedPubMedCentralGoogle Scholar
  114. 114.
    Rosenberg H, Pollock N, Schiemann A et al (2015) Malignant hyperthermia: a review. Orphanet J Rare Dis 10:93CrossRefPubMedPubMedCentralGoogle Scholar
  115. 115.
    Jungbluth H (2007) Central core disease. Orphanet J Rare Dis 2:25CrossRefPubMedPubMedCentralGoogle Scholar
  116. 116.
    Priori SG, Chen SRW (2011) Inherited dysfunction of sarcoplasmic reticulum Ca2+ handling and arrhythmogenesis. Circ Res 108:871–883CrossRefPubMedPubMedCentralGoogle Scholar
  117. 117.
    Ackerman MJ, Priori SG, Willems S et al (2011) HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies this document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA). Heart Rhythm 8(8):1308–1339CrossRefPubMedGoogle Scholar
  118. 118.
    Roux-Buisson N, Cacheux M, Fourest-Lieuvin A et al (2012) Absence of triadin, a protein of the calcium release complex, is responsible for cardiac arrhythmia with sudden death in human. Hum Mol Genet 21:2759–2767CrossRefPubMedPubMedCentralGoogle Scholar
  119. 119.
    Nyegaard M, Overgaard MT, Søndergaard MT et al (2012) Mutations in calmodulin cause ventricular tachycardia and sudden cardiac death. Am J Hum Genet 91:703–712CrossRefPubMedPubMedCentralGoogle Scholar
  120. 120.
    Lieve KV, van der Werf C, Wilde AA (2016) Catecholaminergic polymorphic ventricular tachycardia. Circ J 80:1285–1291CrossRefPubMedGoogle Scholar
  121. 121.
    Murphy NP, Lubbers ER, Mohler PJ (2017) Advancements in the use of gene therapy for cardiac arrhythmia. Heart Rhythm 14:1061–1062CrossRefPubMedGoogle Scholar
  122. 122.
    Rampazzo A, Nava A, Erne P et al (1995) A new locus for arrhythmogenic right ventricular cardiomyopathy (ARVD2) maps to chromosome 1q42-q43. Hum Mol Genet 4:2151–2154CrossRefPubMedGoogle Scholar
  123. 123.
    Corrado D, Link MS, Calkins H (2017) Arrhythmogenic right ventricular cardiomyopathy. N Engl J Med 376:61–72CrossRefPubMedGoogle Scholar
  124. 124.
    Azaouagh A, Churzidse S, Konorza T, Erbel R (2011) Arrhythmogenic right ventricular cardiomyopathy/dysplasia: a review and update. Clin Res Cardiol 100:383–394CrossRefPubMedGoogle Scholar
  125. 125.
    Tong J, McCarthy TV, MacLennan DH (1999) Measurement of resting cytosolic Ca2+ concentrations and Ca2+ store size in HEK-293 cells transfected with malignant hyperthermia or central core disease mutant Ca2+ release channels. J Biol Chem 274:693–702CrossRefPubMedGoogle Scholar
  126. 126.
    Gao L, Balshaw D, Xu L et al (2000) Evidence for a role of the lumenal M3-M4 loop in skeletal muscle Ca(2+) release channel (ryanodine receptor) activity and conductance. Biophys J 79:828–840CrossRefPubMedPubMedCentralGoogle Scholar
  127. 127.
    MacLennan DH, Zvaritch E (2011) Mechanistic models for muscle diseases and disorders originating in the sarcoplasmic reticulum. BBA – Mol Cell Res 1813:948–964Google Scholar
  128. 128.
    Zvaritch E, Depreux F, Kraeva N et al (2007) An Ryr1I4895T mutation abolishes Ca2+ release channel function and delays development in homozygous offspring of a mutant mouse line. Proc Natl Acad Sci USA 104:18537–18542CrossRefPubMedPubMedCentralGoogle Scholar
  129. 129.
    Loy RE, Orynbayev M, Xu L et al (2011) Muscle weakness in Ryr1I4895T/WT knock-in mice as a result of reduced ryanodine receptor Ca2+ ion permeation and release from the sarcoplasmic reticulum. J Gen Physiol 137:43–57CrossRefPubMedPubMedCentralGoogle Scholar
  130. 130.
    Györke I, Gyorke S (1998) Regulation of the cardiac ryanodine receptor channel by luminal Ca2+ involves luminal Ca2+ sensing sites. Biophys J 75:2801–2810CrossRefPubMedPubMedCentralGoogle Scholar
  131. 131.
    Györke S, Terentyev D (2008) Modulation of ryanodine receptor by luminal calcium and accessory proteins in health and cardiac disease. Cardiovasc Res 77:245–255CrossRefPubMedGoogle Scholar
  132. 132.
    Laver DR (2007) Ca2+ stores regulate ryanodine receptor Ca2+ release channels via luminal and cytosolic Ca2+ sites. Biophys J 92:3541–3555CrossRefPubMedPubMedCentralGoogle Scholar
  133. 133.
    Zhang J, Chen B, Zhong X et al (2014) The cardiac ryanodine receptor luminal Ca 2+sensor governs Ca 2+waves, ventricular tachyarrhythmias and cardiac hypertrophy in calsequestrin-null mice. Biochem J 461:99–106CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2017

Authors and Affiliations

  1. 1.Center for Structural BiologyVlaams Instituut voor BiotechnologieBrusselsBelgium
  2. 2.Structural Biology Brussels, Department of Bioengineering SciencesVrije Universiteit BrusselBrusselsBelgium

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