[$Na^+-Ca^{2+}$ Exchange Curtails $Ca^{2+}$before Its Diffusion to Global $Ca^{2+}{_i}$ in the Rat Ventricular Myocyte

  • Ahn, Sung-Wan (Department of Pharmacology and Institute of Basic Medical Science, Yonsei University Wonju-College of Medicine) ;
  • Ko, Chang-Mann (Department of Pharmacology and Institute of Basic Medical Science, Yonsei University Wonju-College of Medicine)
  • Published : 2005.04.21


In the heart, $Na^{+}-Ca^{2+}$ exchange (NCX) is the major $Ca^{2+}$ extrusion mechanism. NCX has been considered as a relaxation mechanism, as it reduces global $[Ca^{2+}]_i$ raised during activation. However, if NCX locates in the close proximity to the ryanodine receptor, then NCX would curtail $Ca^{2+}$ before its diffusion to global $Ca^{2+}_i$ This will result in a global $[Ca^{2+}]_i$ decrease especially during its ascending phase rather than descending phase. Therefore, NCX would decrease the myocardial contractility rather than inducing relaxation in the heart. This possibility was examined in this study by comparing NCX-induced extrusion of $Ca^{2+}$ after its release from SR in the presence and absence of global $Ca^{2+}_i$ transient in the isolated single rat ventricular myocytes by using patch-clamp technique in a whole-cell configuration. Global $Ca^{2+}_i$ transient was controlled by an internal dialysis with different concentrations of BAPTA added in the pipette. During stimulation with a ramp pulse from +100 mV to -100 mV for 200 ms, global $Ca^{2+}_i$ transient was suppressed only mildly, and completely at 1 mmol/L, and 10 mmol/L BAPTA, respectively. In these situations, ryanodine-sensitive inward NCX current was compared using $100{\mu}mol/L$ ryanodine, $Na^+$ depletion, 5 mmol/L $NaCl_2$ and $1{\mu}mol/L$ nifedipine. Surprisingly, the result showed that the ryanodine-sensitive inward NCX current was well preserved after 10 mmol/L BAPTA to 91 % of that obtained after 1 mmol/L BAPTA. From this result, it is concluded that most of the NCX-induced $Ca^{2+}$ extrusion occurs before the $Ca^{2+}$ diffuses to global $Ca^{2+})i$ in the rat ventricular myocyte.


  1. Adachi-Akahane S, Cleemann L, Morad M. Cross-signaling between L-type Ca2+ channels and ryanodine receptors in rat ventricular myocytes. J Gen Physiol 108: 435-54, 1996 https://doi.org/10.1085/jgp.108.5.435
  2. Adachi-Akahane S, Lu L, Li Z, Frank JS, Philipson KD, Morad M. Calcium signaling in transgenic mice overexpressing cardiac Na(+)-Ca2+ exchanger. J Gen Physiol 109: 717-729, 1997 https://doi.org/10.1085/jgp.109.6.717
  3. Argibay JA, Fischmeister R, Hartzell HC. Inactivation, reactivation and pacing dependence of calcium current in frog cardiocytes: correlation with current density. J Physiol 401: 201-226, 1988 https://doi.org/10.1113/jphysiol.1988.sp017158
  4. Bers DM, Bassani JW, Bassani RA. Na-Ca exchange and Ca fluxes during contraction and relaxation in mammalian ventricular muscle. Ann N Y Acad Sci 779: 430-442, 1996 https://doi.org/10.1111/j.1749-6632.1996.tb44818.x
  5. Bers DM, Weber CR. Na/Ca exchange function in intact ventricular myocytes. Ann N Y Acad Sci 976: 500-512, 2002 https://doi.org/10.1111/j.1749-6632.2002.tb04784.x
  6. Carafoli E. Intracellular calcium homeostasis. Annu Rev Biochem 56: 395-433, 1987 https://doi.org/10.1146/annurev.bi.56.070187.002143
  7. Carmeliet E. A fuzzy subsarcolemmal space for intracellular Na+ in cardiac cells? Cardiovasc Res 26: 433-442, 1992 https://doi.org/10.1093/cvr/26.5.433
  8. Chen F, Mottino G, Klitzner TS, Philipson KD, Frank JS. Distribution of the Na+/Ca2+ exchange protein in developing rabbit myocytes. Am J Physiol 268: C1126-C1132, 1995 https://doi.org/10.1152/ajpcell.1995.268.5.C1126
  9. Convery MK, Hancox JC. Comparison of Na+-Ca2+ exchange current elicited from isolated rabbit ventricular myocytes by voltage ramp and step protocols. Pflugers Arch 437: 944-954, 1999 https://doi.org/10.1007/s004240050866
  10. Frank JS, Chen F, Garfinkel A, Moore E, Philipson KD. Immunolocalization of the Na(+)-Ca2+ exchanger in cardiac myocytes. Ann N Y Acad Sci 779: 532-533, 1996 https://doi.org/10.1111/j.1749-6632.1996.tb44829.x
  11. Frank JS, Mottino G, Reid D, Molday RS, Philipson KD. Distribution of the Na(+)-Ca2+ exchange protein in mammalian cardiac myocytes: an immunofluorescence and immunocolloidal gold-labeling study. J Cell Biol 117: 337-345, 1992 https://doi.org/10.1083/jcb.117.2.337
  12. Hobai IA, Hancox JC, Levi AJ. Inhibition by nickel of the L-type Ca channel in guinea pig ventricular myocytes and effect of internal cAMP. Am J Physiol Heart Circ Physiol 279: H692-H701, 2000 https://doi.org/10.1152/ajpheart.2000.279.2.H692
  13. Hobai IA, Maack C, O'Rourke B. Partial inhibition of sodium/calcium exchange restores cellular calcium handling in canine heart failure. Circ Res 95: 292-299, 2004. https://doi.org/10.1161/01.RES.0000136817.28691.2d
  14. Hobai IA, O'Rourke B. Enhanced Ca(2+)-activated Na(+)-Ca(2+) exchange activity in canine pacing-induced heart failure. Circ Res 87: 690-698, 2000 https://doi.org/10.1161/01.RES.87.8.690
  15. Kieval RS, Bloch RJ, Lindenmayer GE, Ambesi A, Lederer WJ. Immunofluorescence localization of the Na-Ca exchanger in heart cells. Am J Physiol 263: C545-C550, 1992 https://doi.org/10.1152/ajpcell.1992.263.2.C545
  16. Langer GA, Peskoff A. Calcium concentration and movement in the diadic cleft space of the cardiac ventricular cell. Biophys J 70: 1169-1182, 1996 https://doi.org/10.1016/S0006-3495(96)79677-7
  17. Langer GA, Peskoff A. Calcium in the cardiac diadic cleft. Implications for sodium-calcium exchange. Ann N Y Acad Sci 779: 408-416, 1996 https://doi.org/10.1111/j.1749-6632.1996.tb44816.x
  18. Langer GA, Rich TL. A discrete Na-Ca exchange-dependent Ca compartment in rat ventricular cells: exchange and localization. Am J Physiol 262: 1149-1153, 1992 https://doi.org/10.1152/ajpcell.1992.262.5.C1149
  19. Langer GA, Wang SY, Rich TL. Localization of the Na/Ca exchangedependent Ca compartment in cultured neonatal rat heart cells. Am J Physiol 268: 119-126, 1995 https://doi.org/10.1152/ajpcell.1995.268.1.C119
  20. Leblanc N, Hume JR. Sodium current-induced release of calcium from cardiac sarcoplasmic reticulum. Science 248: 372-376, 1990 https://doi.org/10.1126/science.2158146
  21. Lederer WJ, Niggli E, Hadley RW. Sodium-calcium exchange in excitable cells: fuzzy space. Science 248: 283, 1990
  22. Mitra R, Morad M. A uniform enzymatic method for dissociation of myocytes from hearts and stomachs of vertebrates. Am J Physiol 249: 1056-1060, 1985
  23. Philipson KD, Nicoll DA, Ottolia M, Quednau BD, Reuter H, John S, Qiu Z. The Na+/Ca2+ exchange molecule: an overview. Ann N Y Acad Sci 976: 1-10, 2002 https://doi.org/10.1111/j.1749-6632.2002.tb04708.x
  24. Reuter H, Han T, Motter C, Philipson KD, Goldhaber JI. Mice overexpressing the cardiac sodium-calcium exchanger: defects in excitation-contraction coupling. J Physiol 554: 779-789, 2004 https://doi.org/10.1113/jphysiol.2003.055046
  25. Scriven DR, Dan P, Moore ED. Distribution of proteins implicated in excitation-contraction coupling in rat ventricular myocytes. Biophys J 79: 2682-2691, 2000 https://doi.org/10.1016/S0006-3495(00)76506-4
  26. Scriven DR, Klimek A, Lee KL, Moore ED. The molecular architecture of calcium microdomains in rat cardiomyocytes. Ann N Y Acad Sci 976: 488-499, 2002
  27. Sham JS. Ca2+ release-induced inactivation of Ca2+ current in rat ventricular myocytes: evidence for local Ca2+ signalling. J Physiol 500: 285-295, 1997 https://doi.org/10.1113/jphysiol.1997.sp022020
  28. Sipido KR, Maes M, Van de Werf F. Low efficiency of Ca2+ entry through the Na(+)-Ca2+ exchanger as trigger for Ca2+ release from the sarcoplasmic reticulum. A comparison between L-type Ca2+ current and reverse-mode Na(+)-Ca2+ exchange. Circ Res 81: 1034-1044, 1997 https://doi.org/10.1161/01.RES.81.6.1034
  29. Sun H, Leblanc N, Nattel S. Mechanisms of inactivation of L-type calcium channels in human atrial myocytes. Am J Physiol 272: H1625-1635, 1997
  30. Thomas MJ, Sjaastad I, Andersen K, Helm PJ, Wasserstrom JA, Sejersted OM, Ottersen OP. Localization and function of the Na+/Ca2+-exchanger in normal and detubulated rat cardiomyocytes. J Mol Cell Cardiol 35: 1325-1337, 2003 https://doi.org/10.1016/j.yjmcc.2003.08.005
  31. Trafford AW, Diaz ME, O'Neill SC, Eisner DA. Comparison of subsarcolemmal and bulk calcium concentration during spontaneous calcium release in rat ventricular myocytes. J Physiol 488: 577-586, 1995 https://doi.org/10.1113/jphysiol.1995.sp020991
  32. Wang SY, Peskoff A, Langer GA. Inner sarcolemmal leaflet Ca(2+) binding: its role in cardiac Na/Ca exchange. Biophys J 70: 2266-2274, 1996 https://doi.org/10.1016/S0006-3495(96)79792-8
  33. Weber CR, Piacentino V, 3rd, Ginsburg KS, Houser SR, Bers DM. Na(+)-Ca(2+) exchange current and submembrane [Ca(2+)] during the cardiac action potential. Circ Res 90: 182-189, 2002 https://doi.org/10.1161/hh0202.103940
  34. Yang Z, Pascarel C, Steele DS, Komukai K, Brette F, Orchard CH. Na+-Ca2+ exchange activity is localized in the T-tubules of rat ventricular myocytes. Circ Res 91: 315-322, 2002 https://doi.org/10.1161/01.RES.0000030180.06028.23