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