T-Tubule Remodelling and Ryanodine Receptor Organization Modulate Sodium-Calcium Exchange

  • Karin R. SipidoEmail author
  • Károly Acsai
  • Gudrun Antoons
  • Virginie Bito
  • Niall Macquaide
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 961)


The Na+/Ca2+ exchanger (NCX) is a key regulator of intracellular Ca2+ in cardiac myocytes, predominantly contributing to Ca2+ removal during the diastolic relaxation process but also modulating excitation-contraction coupling. NCX is preferentially located in the T-tubules and can be close to or within the dyad, where L-type Ca2+ channels face ryanodine receptors (RyRs), the Ca2+ release channels of the sarcoplasmic reticulum. However, especially in larger animals, not all RyRs are in dyads or adjacent to T-tubules, and a substantial fraction of Ca2+ release from the sarcoplasmic reticulum thus occurs at distance from NCX. This chapter deals with the functional consequences of NCX location and how NCX can modulate diastolic and systolic Ca2+ events. The loss of T-tubules and the effects on RyR function and NCX modulation are explored, as well as quantitative measurement of local Ca2+ gradients at the level of the dyadic space.


Ryanodine receptor Na+/Ca2+ exchange T-tubules Hypertrophy Heart Myocardial infarction 



The authors acknowledge support from EC FP7/2007–2013 under grant agreement no. HEALTH-F2-2009-241526, EUTrigTreat (to K.R.S.).


  1. K. Acsai, G. Antoons, L. Livshitz, Y. Rudy, K.R. Sipido, Microdomain [Ca2+] near ryanodine receptors as reported by L-type Ca2+ and Na+/Ca2+ exchange currents. J. Physiol. 589, 2569–2583 (2011)PubMedCrossRefGoogle Scholar
  2. D. Baddeley, D. Crossman, S. Rossberger, J.E. Cheyne, J.M. Montgomery, I.D. Jayasinghe, C. Cremer, M.B. Cannell, C. Soeller, 4D super-resolution microscopy with conventional fluorophores and single wavelength excitation in optically thick cells and tissues. PLoS One 6, e20645 (2011)PubMedCrossRefGoogle Scholar
  3. J.W. Bassani, R.A. Bassani, D.M. Bers, Relaxation in rabbit and rat cardiac cells: species-dependent differences in cellular mechanisms. J. Physiol. 476, 279–293 (1994)PubMedGoogle Scholar
  4. D.M. Bers, S. Despa, J. Bossuyt, Regulation of Ca2+ and Na+ in normal and failing cardiac myocytes. Ann. N. Y. Acad. Sci. 1080, 165–177 (2006)PubMedCrossRefGoogle Scholar
  5. L. Biesmans, N. Macquaide, F.R. Heinzel, V. Bito, G.L. Smith, K.R. Sipido, Subcellular heterogeneity of ryanodine receptor properties in ventricular myocytes with low T-tubule density. PLoS One 6, e25100 (2011)PubMedCrossRefGoogle Scholar
  6. D.J. Crossman, P.N. Ruygrok, C. Soeller, M.B. Cannell, Changes in the organization of excitation-contraction coupling structures in failing human heart. PLoS One 6, e17901 (2011)PubMedCrossRefGoogle Scholar
  7. S. Despa, F. Brette, C.H. Orchard, D.M. Bers, Na/Ca exchange and Na/K-ATPase function are equally concentrated in transverse tubules of rat ventricular myocytes. Biophys. J. 85, 3388–3396 (2003)PubMedCrossRefGoogle Scholar
  8. A.M. Gomez, B. Schwaller, H. Porzig, G. Vassort, E. Niggli, M. Egger, Increased exchange current but normal Ca2+ transport via Na+-Ca2+ exchange during cardiac hypertrophy after myocardial infarction. Circ. Res. 91, 323–330 (2002)PubMedCrossRefGoogle Scholar
  9. F.R. Heinzel, V. Bito, L. Biesmans, M. Wu, E. Detre, F. von Wegner, P. Claus, S. Dymarkowski, F. Maes, J. Bogaert, F. Rademakers, J. D’Hooge, K. Sipido, Remodeling of T-tubules and reduced synchrony of Ca2+ release in myocytes from chronically ischemic myocardium. Circ. Res. 102, 338–346 (2008)PubMedCrossRefGoogle Scholar
  10. R. Larbig, N. Torres, J.H. Bridge, J.I. Goldhaber, K.D. Philipson, Activation of reverse Na+-Ca2+ exchange by the Na+ current augments the cardiac Ca2+ transient: evidence from NCX knockout mice. J. Physiol. 588, 3267–3276 (2010)PubMedCrossRefGoogle Scholar
  11. I. Lenaerts, V. Bito, F.R. Heinzel, R.B. Driesen, P. Holemans, J. D’Hooge, H. Heidbuchel, K.R. Sipido, R. Willems, Ultrastructural and functional remodeling of the coupling between Ca2+ influx and sarcoplasmic reticulum Ca2+ release in right atrial myocytes from experimental persistent atrial fibrillation. Circ. Res. 105, 876–885 (2009)PubMedCrossRefGoogle Scholar
  12. W.E. Louch, V. Bito, F.R. Heinzel, R. Macianskiene, J. Vanhaecke, W. Flameng, K. Mubagwa, K.R. Sipido, Reduced synchrony of Ca2+ release with loss of T-tubules-a comparison to Ca2+ release in human failing cardiomyocytes. Cardiovasc. Res. 62, 63–73 (2004)PubMedCrossRefGoogle Scholar
  13. W.E. Louch, H.K. Mork, J. Sexton, T.A. Stromme, P. Laake, I. Sjaastad, O.M. Sejersted, T-tubule disorganization and reduced synchrony of Ca2+ release in murine cardiomyocytes following myocardial infarction. J. Physiol. 574, 519–533 (2006)PubMedCrossRefGoogle Scholar
  14. F.R. Quinn, S. Currie, A.M. Duncan, S. Miller, R. Sayeed, S.M. Cobbe, G.L. Smith, Myocardial infarction causes increased expression but decreased activity of the myocardial Na+-Ca2+ exchanger in the rabbit. J. Physiol. 553, 229–242 (2003)PubMedCrossRefGoogle Scholar
  15. M.N. Schulson, D.R. Scriven, P. Fletcher, E.D. Moore, Couplons in rat atria form distinct subgroups defined by their molecular partners. J. Cell Sci. 124, 1167–1174 (2011)PubMedCrossRefGoogle Scholar
  16. D.R. Scriven, P. Dan, E.D. Moore, Distribution of proteins implicated in excitation-contraction coupling in rat ventricular myocytes. Biophys. J. 79, 2682–2691 (2000)PubMedCrossRefGoogle Scholar
  17. D.R. Scriven, A. Klimek, K.L. Lee, E.D. Moore, The molecular architecture of calcium microdomains in rat cardiomyocytes. Ann. N. Y. Acad. Sci. 976, 488–499 (2002)PubMedCrossRefGoogle Scholar
  18. T.R. Shannon, D.M. Bers, Integrated Ca2+ management in cardiac myocytes. Ann. N. Y. Acad. Sci. 1015, 28–38 (2004)PubMedCrossRefGoogle Scholar
  19. K.R. Sipido, W.G. Wier, Flux of Ca2+ across the sarcoplasmic reticulum of guinea-pig cardiac cells during excitation-contraction coupling. J. Physiol. 435, 605–630 (1991)PubMedGoogle Scholar
  20. K.R. Sipido, P.G. Volders, S.H. de Groot, F. Verdonck, F. Van de Werf, H.J. Wellens, M.A. Vos, Enhanced Ca2+ release and Na/Ca exchange activity in hypertrophied canine ventricular myocytes: potential link between contractile adaptation and arrhythmogenesis. Circulation 102, 2137–2144 (2000)PubMedCrossRefGoogle Scholar
  21. K.R. Sipido, P.G. Volders, M.A. Vos, F. Verdonck, Altered Na/Ca exchange activity in cardiac hypertrophy and heart failure: a new target for therapy? Cardiovasc. Res. 53, 782–805 (2002a)PubMedCrossRefGoogle Scholar
  22. K.R. Sipido, P.G. Volders, M. Schoenmakers, S.H. De Groot, F. Verdonck, M.A. Vos, Role of the Na/Ca exchanger in arrhythmias in compensated hypertrophy. Ann. N. Y. Acad. Sci. 976, 438–445 (2002b)PubMedCrossRefGoogle Scholar
  23. K.R. Sipido, A. Varro, D. Eisner, Sodium calcium exchange as a target for antiarrhythmic therapy. Handb. Exp. Pharmacol. 171, 159–199 (2006)PubMedCrossRefGoogle Scholar
  24. L.S. Song, E.A. Sobie, S. McCulle, W.J. Lederer, C.W. Balke, H. Cheng, Orphaned ryanodine receptors in the failing heart. Proc. Natl. Acad. Sci. U. S. A. 103, 4305–4310 (2006)PubMedCrossRefGoogle Scholar
  25. A.W. Trafford, M.E. Diaz, S.C. O’Neill, D.A. Eisner, Comparison of subsarcolemmal and bulk calcium concentration during spontaneous calcium release in rat ventricular myocytes. J. Physiol. 488, 577–586 (1995)PubMedGoogle Scholar
  26. A. Varro, N. Negretti, S.B. Hester, D.A. Eisner, An estimate of the calcium content of the sarcoplasmic reticulum in rat ventricular myocytes. Pflugers Arch. 423, 158–160 (1993)PubMedCrossRefGoogle Scholar
  27. F. Verdonck, P.G. Volders, M.A. Vos, K.R. Sipido, Intracellular Na+ and altered Na+ transport mechanisms in cardiac hypertrophy and failure. J. Mol. Cell. Cardiol. 35, 5–25 (2003)PubMedCrossRefGoogle Scholar
  28. C.R. Weber, V. Piacentino 3rd, K.S. Ginsburg, S.R. Houser, D.M. Bers, Na+-Ca2+ exchange current and submembrane [Ca2+] during the cardiac action potential. Circ. Res. 90, 182–189 (2002)PubMedCrossRefGoogle Scholar
  29. S. Wei, A. Guo, B. Chen, W. Kutschke, Y.P. Xie, K. Zimmerman, R.M. Weiss, M.E. Anderson, H. Cheng, L.S. Song, T-tubule remodeling during transition from hypertrophy to heart failure. Circ. Res. 107, 520–531 (2010)PubMedCrossRefGoogle Scholar
  30. Z. Yang, C. Pascarel, D.S. Steele, K. Komukai, F. Brette, C.H. Orchard, Na+-Ca2+ exchange activity is localized in the T-tubules of rat ventricular myocytes. Circ. Res. 91, 315–322 (2002)PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Karin R. Sipido
    • 1
    Email author
  • Károly Acsai
    • 2
  • Gudrun Antoons
    • 1
    • 3
  • Virginie Bito
    • 1
  • Niall Macquaide
    • 1
  1. 1.Laboratory of Experimental Cardiology, Department of Cardiovascular DiseasesUniversity of LeuvenLeuvenBelgium
  2. 2.Division of Cardiovascular PharmacologyHungarian Academy of SciencesSzegedHungary
  3. 3.Department of CardiologyMedical University of GrazGrazAustria

Personalised recommendations