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Modification of cardiac RYR2 gating by a peptide from the central domain of the RYR2

  • Research Article
  • Published:
Central European Journal of Biology

Abstract

The effect of a domain peptide DPCPVTc from the central region of the RYR2 on ryanodine receptors from rat heart has been examined in planar lipid bilayers. At a zero holding potential and at 8 mmol L−1 luminal Ca2+ concentration, DPCPVTc induced concentrationdependent activation of the ryanodine receptor that led up to 20-fold increase of PO at saturating DPCPVTc concentrations. DPCPVTc prolonged RyR2 openings and increased RyR2 opening frequency. At all peptide concentrations the channels displayed large variability in open probability, open time and frequency of openings. With increasing peptide concentration, the fraction of high open probability records increased together with their open time. The closed times of neither low- nor high-open probability records depended on peptide concentration. The concentration dependence of all gating parameters had EC50 of 20 μmol L−1 and a Hill slope of 2. Comparison of the effects of DPCPVTc with the effects of ATP and cytosolic Ca2+ suggests that activation does not involve luminal feed-through and is not caused by modulation of the cytosolic activation A-site. The data suggest that although “domain unzipping” by DPCPVTc occurs in both modes of RyR activity, it affects RyR gating only when the channel resides in the H-mode of activity.

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References

  1. Yano M., Yamamoto T., Ikeda Y., Matsuzaki M., Mechanisms of Disease: ryanodine receptor defects in heart failure and fatal arrhythmia, Nat. Clin. Pract. Cardiovasc. Med., 2006, 3, 43–52

    Article  PubMed  CAS  Google Scholar 

  2. Bhat M.B., Zhao J., Takeshima H., Ma J., Functional calcium release channel formed by the carboxylterminal portion of ryanodine receptor, Biophys. J. 1997, 73, 1329–1336.

    Article  PubMed  CAS  Google Scholar 

  3. Durham W.J., Wehrens X.H., Sood S., Hamilton S.L., Diseases associated with altered ryanodine receptor activity, Sub-cellular Biochem., 2007, 45, 273–321

    Article  CAS  Google Scholar 

  4. Lanner J.T., Ryanodine receptor physiology and its role in disease, Adv. Exp. Med. Biol. 2012, 740, 217–234

    Article  PubMed  CAS  Google Scholar 

  5. Ikemoto N., Yamamoto T., Regulation of calcium release by interdomain interaction within ryanodine receptors, Front. Biosci., 2002, 7, d671–683

    Article  PubMed  CAS  Google Scholar 

  6. Laver D.R., Honen B.N., Lamb G.D., Ikemoto N., A domain peptide of the cardiac ryanodine receptor regulates channel sensitivity to luminal Ca2+ via cytoplasmic Ca2+ sites, Eur. Biophys. J., 2008, 37, 455–467

    Article  PubMed  CAS  Google Scholar 

  7. Gaburjakova J., Gaburjakova M., Comparison of the effects exerted by luminal Ca2+ on the sensitivity of the cardiac ryanodine receptor to caffeine and cytosolic Ca2+, J. Membr. Biol., 2006, 212, 17–28

    Article  PubMed  CAS  Google Scholar 

  8. Rousseau E., Smith J.S., Henderson J.S., Meissner G., Single channel and 45 Ca2+ flux measurements of the cardiac sarcoplasmic reticulum calcium channel, Biophys. J., 1986, 50, 1009–1014

    Article  PubMed  CAS  Google Scholar 

  9. Tencerova B., Zahradnikova A., Gaburjakova J., Gaburjakova M., Luminal Ca2+ controls activation of the cardiac ryanodine receptor by ATP, J. Gen. Physiol., 2012, 140, 93–108

    Article  PubMed  CAS  Google Scholar 

  10. Zahradnikova A., Zahradnik I., Description of modal gating of the cardiac calcium release channel in planar lipid membranes, Biophys. J., 1995, 69, 1780–1788

    Article  PubMed  CAS  Google Scholar 

  11. Tiso N., Stephan D.A., Nava A., Bagattin A., Devaney J.M., Stanchi F., et al., Identification of mutations in the cardiac ryanodine receptor gene in families affected with arrhythmogenic right ventricular cardiomyopathy type 2 (ARVD2), Hum. Mol. Genet. 2001, 10, 189–194

    Article  PubMed  CAS  Google Scholar 

  12. Tester D.J., Kopplin L.J., Will M.L., Ackerman M.J., Spectrum and prevalence of cardiac ryanodine receptor (RyR2) mutations in a cohort of unrelated patients referred explicitly for long QT syndrome genetic testing, Heart Rhythm., 2005, 2, 1099–1105

    Article  PubMed  Google Scholar 

  13. Bagattin A., Veronese C., Bauce B., Wuyts W., Settimo L., Nava A., et al., Denaturing HPLC-based approach for detecting RYR2 mutations involved in malignant arrhythmias, Clin. Chem., 2004, 50, 1148–1155

    Article  PubMed  CAS  Google Scholar 

  14. Medeiros-Domingo A., Bhuiyan Z.A., Tester D.J., Hofman N., Bikker H., Van Tintelen J.P., et al., The RYR2-encoded ryanodine receptor/calcium release channel in patients diagnosed previously with either catecholaminergic polymorphic ventricular tachycardia or genotype negative, exerciseinduced long QT syndrome: a comprehensive open reading frame mutational analysis, J. Am. Coll. Cardiol., 2009, 54, 2065–2074

    Article  PubMed  CAS  Google Scholar 

  15. Bauce B., Rampazzo A., Basso C., Bagattin A., Daliento L., Tiso N., et al., Screening for ryanodine receptor type 2 mutations in families with effortinduced polymorphic ventricular arrhythmias and sudden death: early diagnosis of asymptomatic carriers, J. Am. Coll. Cardiol., 2002, 40, 341–349

    Article  PubMed  CAS  Google Scholar 

  16. Postma A.V., Denjoy I., Kamblock J., Alders M., Lupoglazoff J.M., Vaksmann G., et al., Catecholaminergic polymorphic ventricular tachycardia: RYR2 mutations, bradycardia, and follow up of the patients, J. Med. Genet. 2005, 42, 863–870

    Article  PubMed  CAS  Google Scholar 

  17. Aizawa Y., Ueda K., Komura S., Washizuka T., Chinushi M., Inagaki N., et al., A novel mutation in FKBP12.6 binding region of the human cardiac ryanodine receptor gene (R2401H) in a Japanese patient with catecholaminergic polymorphic ventricular tachycardia, Int. J. Cardiol. 2005, 99, 343–345

    Article  PubMed  Google Scholar 

  18. Creighton W., Virmani R., Kutys R., Burke A., Identification of novel missense mutations of cardiac ryanodine receptor gene in exerciseinduced sudden death at autopsy, J. Mol. Diagnostics, 2006, 8, 62–67

    Article  CAS  Google Scholar 

  19. Choi G., Kopplin L.J., Tester D.J., Will M.L., Haglund C.M., Ackerman M.J., Spectrum and frequency of cardiac channel defects in swimmingtriggered arrhythmia syndromes, Circulation, 2004, 110, 2119–2124

    Article  PubMed  Google Scholar 

  20. Beckmann B.M., Wilde A.A., Kaab S., Dual inheritance of sudden death from cardiovascular causes, N. Engl. J. Med., 2008, 358, 2077–2078

    Article  PubMed  CAS  Google Scholar 

  21. Ikemoto N., Yamamoto T., Postulated role of interdomain interaction within the ryanodine receptor in Ca(2+) channel regulation, Trends Cardiovasc. Med., 2000, 10, 310–316

    Article  PubMed  CAS  Google Scholar 

  22. Yamamoto T., El-Hayek R., Ikemoto N., Postulated role of interdomain interaction within the ryanodine receptor in Ca(2+) channel regulation, J. Biol. Chem., 2000, 275, 11618–11625

    Article  PubMed  CAS  Google Scholar 

  23. Yamamoto T., Ikemoto N., Peptide probe study of the critical regulatory domain of the cardiac ryanodine receptor, Biochem. Biophys. Res. Commun. 2002, 291, 1102–1108.

    Article  PubMed  CAS  Google Scholar 

  24. Kobayashi S., Yamamoto T., Parness J., Ikemoto N., Antibody probe study of Ca2+ channel regulation by interdomain interaction within the ryanodine receptor, Biochem. J., 2004, 380, 561–569

    Article  PubMed  CAS  Google Scholar 

  25. Yamamoto T., Yano M., Xu X., Uchinoumi H., Tateishi H., Mochizuki M., et al., Identification of target domains of the cardiac ryanodine receptor to correct channel disorder in failing hearts, Circulation, 2008, 117, 762–772

    Article  PubMed  CAS  Google Scholar 

  26. Suetomi T., Yano M., Uchinoumi H., Fukuda M., Hino A., Ono M., et al., Mutation-linked defective interdomain interactions within ryanodine receptor cause aberrant Ca2+ release leading to catecholaminergic polymorphic ventricular tachycardia, Circulation, 2011, 124, 682–694

    Article  PubMed  CAS  Google Scholar 

  27. Zahradnikova A., Zahradnik I., Modification of cardiac Ca2+ release channel gating by DIDS, Pflugers Arch., 1993, 425, 555–557

    Article  PubMed  CAS  Google Scholar 

  28. Zahradnikova A., Zahradnik I., Construction of calcium release sites in cardiac myocytes, Front Physiol., 2012, 3, 322

    Article  PubMed  Google Scholar 

  29. Zahradnikova A., Valent I., Zahradnik I., Frequency and release flux of calcium sparks in rat cardiac myocytes: a relation to RYR gating, J. Gen. Physiol., 2010, 136, 101–116

    Article  PubMed  CAS  Google Scholar 

  30. Zahradnik I., Gyorke S., Zahradnikova A., Calcium activation of ryanodine receptor channels—reconciling RyR gating models with tetrameric channel structure, J. Gen. Physiol., 2005, 126, 515–527

    Article  PubMed  CAS  Google Scholar 

  31. Janicek R., Zahradnikova A.,Jr., Polakova E., Pavelkova J., Zahradnik I., Zahradnikova A., Calcium spike variability in cardiac myocytes results from activation of small cohorts of ryanodine receptor 2 channels, J. Physiol., 2012, 590, 5091–5106

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Muscle Cell Research, Institute of Molecular Physiology and Genetics, Slovak Academy of Sciences, 833 34, Bratislava, Slovakia

    Andrea Faltinová & Alexandra Zahradníková

  2. Department of Biochemistry and Structural Biology, Institute of Molecular Biology, Slovak Academy of Sciences, 845 51, Bratislava, Slovakia

    Andrea Faltinová & Alexandra Zahradníková

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  1. Andrea Faltinová
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  2. Alexandra Zahradníková
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Correspondence to Alexandra Zahradníková.

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Faltinová, A., Zahradníková, A. Modification of cardiac RYR2 gating by a peptide from the central domain of the RYR2. cent.eur.j.biol. 8, 1164–1171 (2013). https://doi.org/10.2478/s11535-013-0241-6

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  • DOI: https://doi.org/10.2478/s11535-013-0241-6

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