Livin’ with NCX and Lovin’ It: A 45 Year Romance

  • Mordecai P. BlausteinEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 961)


This conference commemorates, almost to the day, the 45th anniversary of the discovery of the Na+/Ca2+ exchanger (NCX). The discovery was serendipitous, as is so often the case with scientific breakthroughs. Indeed, that is what is so fascinating and romantic about scientific research. I will describe the discovery of NCX, but will begin by explaining how I got there, and will then discuss how the discovery influenced my career path.


Cardiotonic steroids Hypertension PLasmERosomes Synaptosomes Vascular smooth muscle 



I thank Suzanne Ventura for assistance with the manuscript. Supported by NIH/NHLB, NCX. Supported by NIH/NHLBI grants HL-045215, HL-078870, and HL-107555 and NIH/NINDS grant NS-16106.


  1. J. Altamirano, Y. Li, J. DeSantiago, V. Piacentino 3rd, S.R. Houser, D.M. Bers, The inotropic effect of cardioactive glycosides in ventricular myocytes requires Na+-Ca2+ exchanger function. J. Physiol. 575, 845–854 (2006)PubMedCrossRefGoogle Scholar
  2. A. Arnon, J.M. Hamlyn, M.P. Blaustein, Na+ entry via store-operated channels modulates Ca2+ signaling in arterial myocytes. Am. J. Physiol. Cell Physiol. 278, C163–C173 (2000a)PubMedGoogle Scholar
  3. A. Arnon, J.M. Hamlyn, M.P. Blaustein, Ouabain augments Ca2+ transients in arterial smooth muscle without raising cytosolic Na+. Am. J. Physiol. Heart Circ. Physiol. 279, H679–H691 (2000b)PubMedGoogle Scholar
  4. Y.M. Bae, A. Kim, Y.J. Lee, W. Lim, Y.H. Noh, E.J. Kim, J. Kim, T.K. Kim, S.W. Park, B. Kim, S.I. Cho, D.K. Kim, W.K. Ho, Enhancement of receptor-operated cation current and TRPC6 expression in arterial smooth muscle cells of deoxycorticosterone acetate-salt hypertensive rats. J. Hypertens. 25, 809–817 (2007)PubMedCrossRefGoogle Scholar
  5. P.F. Baker, M.P. Blaustein, A.L. Hodgkin, R.A. Steinhardt, The influence of calcium on sodium efflux in squid axons. J. Physiol. 200, 431–458 (1969)PubMedGoogle Scholar
  6. M.P. Blaustein, Barbiturates block sodium and potassium conductance increases in voltage- clamped lobster axons. J. Gen. Physiol. 51, 293–307 (1968)PubMedCrossRefGoogle Scholar
  7. M.P. Blaustein, The interrelationship between sodium and calcium fluxes across cell membranes. Rev. Physiol. Biochem. Pharmacol. 70, 33–82 (1974)PubMedCrossRefGoogle Scholar
  8. M.P. Blaustein, Sodium ions, calcium ions, blood pressure regulation, and hypertension: a reassessment and a hypothesis. Am. J. Physiol. 232, C165–C173 (1977)PubMedGoogle Scholar
  9. M.P. Blaustein, D.E. Goldman, Action of anionic and cationic nerve-blocking agents: experiment and interpretation. Science 153, 429–432 (1966)PubMedCrossRefGoogle Scholar
  10. M.P. Blaustein, J.M. Goldring, Membrane potentials in pinched-off presynaptic nerve terminals monitored with a fluorescent probe: evidence that synaptosomes have potassium diffusion potentials. J. Physiol. 247, 589–615 (1975)PubMedGoogle Scholar
  11. M.P. Blaustein, J.M. Hamlyn, Signaling mechanisms that link salt retention to hypertension: endogenous ouabain, the Na+ pump, the Na+/Ca2+ exchanger and TRPC proteins. Biochim. Biophys. Acta 1802, 1219–1229 (2010)PubMedCrossRefGoogle Scholar
  12. M.P. Blaustein, W.J. Lederer, Sodium/calcium exchange: its physiological implications. Physiol. Rev. 79, 763–854 (1999)PubMedGoogle Scholar
  13. M.P. Blaustein, W.P. Wiesmann, Effect of sodium ions on calcium movements in isolated synaptic terminals. Proc. Natl. Acad. Sci. U. S. A. 66, 664–671 (1970)PubMedCrossRefGoogle Scholar
  14. M.P. Blaustein, R.S. Rogowski, M.J. Schneider, B.K. Krueger, Polypeptide toxins from the venoms of Old World and New World scorpions preferentially block different potassium channels. Mol. Pharmacol. 40, 932–942 (1991)PubMedGoogle Scholar
  15. M.P. Blaustein, A. Ambesi, R.J. Bloch, W.F. Goldman, M. Juhaszova, G.E. Lindenmayer, D.N. Weiss, Regulation of vascular smooth muscle contractility: roles of the sarcoplasmic reticulum (SR) and the sodium/calcium exchanger. Jpn. J. Pharmacol. 58(Suppl 2), 107P–114P (1992)PubMedGoogle Scholar
  16. M.P. Blaustein, M. Juhaszova, V.A. Golovina, The cellular mechanism of action of cardiotonic steroids: a new hypothesis. Clin. Exp. Hypertens. 20, 691–703 (1998)PubMedCrossRefGoogle Scholar
  17. M.P. Blaustein, F.H. Leenen, L. Chen, V.A. Golovina, J.M. Hamlyn, T.L. Pallone, J.W. Van Huysse, J. Zhang, W.G. Wier, How NaCl raises blood pressure: a new paradigm for the pathogenesis of salt-dependent hypertension. Am. J. Physiol. Heart. Circ. Physiol. 302, H3031-H1049 (2012)Google Scholar
  18. Y.Q. Cao, R.W. Tsien, Different relationship of N- and P/Q-type Ca2+ channels to channel- interacting slots in controlling neurotransmission at cultured hippocampal synapses. J. Neurosci. 30, 4536–4546 (2010)PubMedCrossRefGoogle Scholar
  19. W.A. Catterall, Structure and function of neuronal Ca2+ channels and their role in neurotransmitter release. Cell. Calcium. 24, 307–323 (1998)PubMedCrossRefGoogle Scholar
  20. P. Drapeau, M.P. Blaustein, Initial release of [3 H]dopamine from rat striatal synaptosomes: correlation with calcium entry. J. Neurosci. 3, 703–713 (1983)PubMedGoogle Scholar
  21. P. Eder, M. Poteser, C. Romanin, K. Groschner, Na+ entry and modulation of Na+/Ca2+ exchange as a key mechanism of TRPC signaling. Pflugers Arch. 451, 99–104 (2005)PubMedCrossRefGoogle Scholar
  22. G. Fontana, R.S. Rogowski, M.P. Blaustein, Kinetic properties of the sodium-calcium exchanger in rat brain synaptosomes. J. Physiol. 485, 349–364 (1995)PubMedGoogle Scholar
  23. R.C. Fried, M.P. Blaustein, Synaptic vesicle recycling in synaptosomes in vitro. Nature 261, 255–256 (1976)PubMedCrossRefGoogle Scholar
  24. F.R. Giachini, R.C. Tostes, Does Na+ really play a role in Ca2+ homeostasis in hypertension? Am. J. Physiol. Heart Circ. Physiol. 299, H602–H604 (2010)PubMedCrossRefGoogle Scholar
  25. V.A. Golovina, Visualization of localized store-operated calcium entry in mouse astrocytes. Close proximity to the endoplasmic reticulum. J. Physiol. 564, 737–749 (2005)PubMedCrossRefGoogle Scholar
  26. A.C. Guyton, Dominant role of the kidneys and accessory role of whole-body autoregulation in the pathogenesis of hypertension. Am. J. Hypertens. 2, 575–585 (1989)PubMedGoogle Scholar
  27. J.M. Hamlyn, M.P. Blaustein, S. Bova, D.W. DuCharme, D.W. Harris, F. Mandel, W.R. Mathews, J.H. Ludens, Identification and characterization of a ouabain-like compound from human plasma. Proc. Natl. Acad. Sci. U. S. A. 88, 6259–6263 (1991)PubMedCrossRefGoogle Scholar
  28. A.L. Hodgkin, R.D. Keynes, Experiments on the injection of substances into squid giant axons by means of a microsyringe. J. Physiol. 131, 592–616 (1956)PubMedGoogle Scholar
  29. T. Iwamoto, S. Kita, J. Zhang, M.P. Blaustein, Y. Arai, S. Yoshida, K. Wakimoto, I. Komuro, T. Katsuragi, Salt-sensitive hypertension is triggered by Ca2+ entry via Na+/Ca2+ exchanger type-1 in vascular smooth muscle. Nature Med. 10, 1193–1199 (2004)PubMedCrossRefGoogle Scholar
  30. M. Juhaszova, M.P. Blaustein, Distinct distribution of different Na+ pump alpha subunit isoforms in plasmalemma. Physiological implications. Ann. N. Y. Acad. Sci. 834, 524–536 (1997a)PubMedCrossRefGoogle Scholar
  31. M. Juhaszova, M.P. Blaustein, Na+ pump low and high ouabain affinity alpha subunit isoforms are differently distributed in cells. Proc. Natl. Acad. Sci. U. S. A. 94, 1800–1805 (1997b)PubMedCrossRefGoogle Scholar
  32. M. Juhaszova, A. Ambesi, G.E. Lindenmayer, R.J. Bloch, M.P. Blaustein, Na+-Ca2+ exchanger in arteries: identification by immunoblotting and immunofluorescence microscopy. Am. J. Physiol. 266, C234–C242 (1994)PubMedGoogle Scholar
  33. A. Kawamura, J. Guo, Y. Itagaki, C. Bell, Y. Wang, G.T. Haupert Jr., S. Magil, R.T. Gallagher, N. Berova, K. Nakanishi, On the structure of endogenous ouabain. Proc. Natl. Acad. Sci. U. S. A. 96, 6654–6659 (1999)PubMedCrossRefGoogle Scholar
  34. N.C. Kendrick, M.P. Blaustein, R.C. Fried, R.W. Ratzlaff, ATP-dependent calcium storage in presynaptic nerve terminals. Nature 265, 246–248 (1977)PubMedCrossRefGoogle Scholar
  35. B.K. Krueger, M.P. Blaustein, R.W. Ratzlaff, Sodium channels in presynaptic nerve terminals. Regulation by neurotoxins. J. Gen. Physiol. 76, 287–313 (1980)PubMedCrossRefGoogle Scholar
  36. J. Laredo, B.P. Hamilton, J.M. Hamlyn, Ouabain is secreted by bovine adrenocortical cells. Endocrinology 135, 794–797 (1994)PubMedCrossRefGoogle Scholar
  37. M.Y. Lee, H. Song, J. Nakai, M. Ohkura, M.I. Kotlikoff, S.P. Kinsey, V.A. Golovina, M.P. Blaustein, Local subplasma membrane Ca2+ signals detected by a tethered Ca2+ sensor. Proc. Natl. Acad. Sci. U. S. A. 103, 13232–13237 (2006)PubMedCrossRefGoogle Scholar
  38. L. Lencesova, A. O’Neill, W.G. Resneck, R.J. Bloch, M.P. Blaustein, Plasma membrane- cytoskeleton-endoplasmic reticulum complexes in neurons and astrocytes. J. Biol. Chem. 279, 2885–2893 (2004)PubMedCrossRefGoogle Scholar
  39. J. Liu, Z.J. Xie, The sodium pump and cardiotonic steroids-induced signal transduction protein kinases and calcium-signaling microdomain in regulation of transporter trafficking. Biochim. Biophys. Acta 1802, 1237–1245 (2010)PubMedCrossRefGoogle Scholar
  40. L. Liu, X. Zhao, S.V. Pierre, A. Askari, Association of PI3K-Akt signaling pathway with digitalis- induced hypertrophy of cardiac myocytes. Am. J. Physiol. Cell Physiol. 293, C1489–C1497 (2007)PubMedCrossRefGoogle Scholar
  41. D. Liu, D. Yang, H. He, X. Chen, T. Cao, X. Feng, L. Ma, Z. Luo, L. Wang, Z. Yan, Z. Zhu, M. Tepel, Increased transient receptor potential canonical type 3 channels in vasculature from hypertensive rats. Hypertension 53, 70–76 (2009)PubMedCrossRefGoogle Scholar
  42. L. Liu, A.V. Ivanov, M.E. Gable, F. Jolivel, G.A. Morrill, A. Askari, Comparative properties of caveolar and noncaveolar preparations of kidney Na+/K+-ATPase. Biochemistry 50, 8664–8673 (2011)PubMedCrossRefGoogle Scholar
  43. H.C. Luttgau, R. Niedergerke, The antagonism between Ca and Na ions on the frog’s heart. J. Physiol. 143, 486–505 (1958)PubMedGoogle Scholar
  44. P. Manunta, J. Hamilton, A.C. Rogowski, B.P. Hamilton, J.M. Hamlyn, Chronic hypertension induced by ouabain but not digoxin in the rat: antihypertensive effect of digoxin and digitoxin. Hypertens. Res. 23(Suppl), S77–S85 (2000)PubMedCrossRefGoogle Scholar
  45. J.W. Moore, M.P. Blaustein, N.C. Anderson, T. Narahashi, Basis of tetrodotoxin’s selectivity in blockage of squid axons. J. Gen. Physiol. 50, 1401–1411 (1967)PubMedCrossRefGoogle Scholar
  46. R.A. Murphy, Contraction of muscle cells, in Physiology, ed. by R.M. Berne, M.N. Levy, 2nd edn. (Mosby, Washington, DC, 1988), pp. 315–342Google Scholar
  47. R.A. Murphy, Smooth muscle, in Physiology, ed. by R.M. Berne, M.N. Levy, 3rd edn. (Mosby Year Book, St. Louis, 1993), pp. 309–324Google Scholar
  48. D.A. Nachshen, M.P. Blaustein, The effects of some organic “calcium antagonists” on calcium influx in presynaptic nerve terminals. Mol. Pharmacol. 16, 576–586 (1979)PubMedGoogle Scholar
  49. D.A. Nicoll, S. Longoni, K.D. Philipson, Molecular cloning and functional expression of the cardiac sarcolemmal Na+-Ca2+ exchanger. Science 250, 562–565 (1990)PubMedCrossRefGoogle Scholar
  50. G. Owsianik, K. Talavera, T. Voets, B. Nilius, Permeation and selectivity of TRP channels. Annu. Rev. Physiol. 68, 685–717 (2006)PubMedCrossRefGoogle Scholar
  51. D. Poburko, C.H. Liao, V.S. Lemos, E. Lin, Y. Maruyama, W.C. Cole, C. van Breemen, Transient receptor potential channel 6-mediated, localized cytosolic [Na+] transients drive Na+/Ca2+ exchanger-mediated Ca2+ entry in purinergically stimulated aorta smooth muscle cells. Circ. Res. 101, 1030–1038 (2007)PubMedCrossRefGoogle Scholar
  52. M.V. Pulina, A. Zulian, R. Berra-Romani, O. Beskina, A. Mazzocco-Spezzia, S.G. Baryshnikov, I. Papparella, J.M. Hamlyn, M.P. Blaustein, V.A. Golovina, Upregulation of Na+ and Ca2+ transporters in arterial smooth muscle from ouabain-induced hypertensive rats. Am. J. Physiol. Heart Circ. Physiol. 298, H263–H274 (2010)PubMedCrossRefGoogle Scholar
  53. H. Reuter, N. Seitz, The dependence of calcium efflux from cardiac muscle on temperature and external ion composition. J. Physiol. 195, 451–470 (1968)PubMedGoogle Scholar
  54. H. Reuter, M.P. Blaustein, G. Haeusler, Na-Ca exchange and tension development in arterial smooth muscle. Philos. Trans. R. Soc. Lond. B Biol. Sci. 265, 87–94 (1973)PubMedCrossRefGoogle Scholar
  55. H. Reuter, S.A. Henderson, T. Han, R.S. Ross, J.I. Goldhaber, K.D. Philipson, The Na+-Ca2+ exchanger is essential for the action of cardiac glycosides. Circ. Res. 90, 305–308 (2002)PubMedCrossRefGoogle Scholar
  56. G. Rossi, P. Manunta, J.M. Hamlyn, E. Pavan, R. De Toni, A. Semplicini, A.C. Pessina, Immunoreactive endogenous ouabain in primary aldosteronism and essential hypertension: relationship with plasma renin, aldosterone and blood pressure levels. J. Hypertens. 13, 1181–1191 (1995)PubMedCrossRefGoogle Scholar
  57. R. Schneider, V. Wray, M. Nimtz, W.D. Lehmann, U. Kirch, R. Antolovic, W. Schoner, Bovine adrenals contain, in addition to ouabain, a second inhibitor of the sodium pump. J. Biol. Chem. 273, 784–792 (1998)PubMedCrossRefGoogle Scholar
  58. J.C. Skou, The influence of some cations on an adenosine triphosphatase from peripheral nerves. Biochim. Biophys. Acta 23, 394–401 (1957)PubMedCrossRefGoogle Scholar
  59. A.P. Somlyo, A.V. Somlyo, Signal transduction and regulation in smooth muscle. Nature 372, 231–236 (1994)PubMedCrossRefGoogle Scholar
  60. A.P. Somlyo, R. Broderick, A.V. Somlyo, Calcium and sodium in vascular smooth muscle. Ann. N. Y. Acad. Sci. 488, 228–239 (1986)PubMedCrossRefGoogle Scholar
  61. H. Song, M.Y. Lee, S.P. Kinsey, D.J. Weber, M.P. Blaustein, An N-terminal sequence targets and tethers Na+ pump α2 subunits to specialized plasma membrane microdomains. J. Biol. Chem. 281, 12929–12940 (2006)PubMedCrossRefGoogle Scholar
  62. A. Sophocleous, I. Elmatzoglou, A. Souvatzoglou, Circulating endogenous digitalis-like factor(s) (EDLF) in man is derived from the adrenals and its secretion is ACTH-dependent. J. Endocrinol. Invest. 26, 668–674 (2003)PubMedGoogle Scholar
  63. M. Tamura, F. Konishi, M. Sakakibara, T. Inagami, Large scale purification of an endogenous Na+/K+-pump inhibitor from bovine adrenal glands, in The Sodium Pump: Structure, Mechanism, Hormonal Control and Its Role in Disease, ed. by E. Bamberg, W. Schoner (Steinkopff, Darmstadt, 1994), pp. 763–766Google Scholar
  64. H. Tanaka, H. Shimada, I. Namekata, T. Kawanishi, N. Iida-Tanaka, K. Shigenobu, Involvement of the Na+/Ca2+ exchanger in ouabain-induced inotropy and arrhythmogenesis in guinea-pig myocardium as revealed by SEA0400. J. Pharmacol. Sci. 103, 241–246 (2007)PubMedCrossRefGoogle Scholar
  65. S. Taniguchi, K. Furukawa, S. Sasamura, Y. Ohizumi, K. Seya, S. Motomura, Gene expression and functional activity of sodium/calcium exchanger enhanced in vascular smooth muscle cells of spontaneously hypertensive rats. J. Cardiovasc. Pharmacol. 43, 629–637 (2004)PubMedCrossRefGoogle Scholar
  66. C. van Breemen, S. Lukeman, P. Leijten, H. Yamamoto, R. Loutzenhiser, The role of superficial SR in modulating force development induced by Ca entry into arterial smooth muscle. J. Cardiovasc. Pharmacol. 8(Suppl 8), S111–S116 (1986)PubMedCrossRefGoogle Scholar
  67. C. van Breemen, Q. Chen, I. Laher, Superficial buffer barrier function of smooth muscle sarcoplasmic reticulum. Trends Pharmacol. Sci. 16, 98–105 (1995)PubMedCrossRefGoogle Scholar
  68. R. Vemuri, M.E. Haberland, D. Fong, K.D. Philipson, Identification of the cardiac sarcolemmal Na+-Ca2+ exchanger using monoclonal antibodies. J. Membr. Biol. 118, 279–283 (1990)PubMedCrossRefGoogle Scholar
  69. W.G. Wier, P. Hess, Excitation-contraction coupling in cardiac Purkinje fibers. Effects of cardiotonic steroids on the intracellular [Ca2+] transient, membrane potential, and contraction. J. Gen. Physiol. 83, 395–415 (1984)PubMedCrossRefGoogle Scholar
  70. Z. Xie, A. Askari, Na+/K+-ATPase as a signal transducer. Eur. J. Biochem. 269, 2434–2439 (2002)PubMedCrossRefGoogle Scholar
  71. Y. Yu, I. Fantozzi, C.V. Remillard, J.W. Landsberg, N. Kunichika, O. Platoshyn, D.D. Tigno, P.A. Thistlethwaite, L.J. Rubin, J.X. Yuan, Enhanced expression of transient receptor potential channels in idiopathic pulmonary arterial hypertension. Proc. Natl. Acad. Sci. U. S. A. 101, 13861–13866 (2004)PubMedCrossRefGoogle Scholar
  72. Z. Zhang, C. Cao, W. Lee-Kwon, T.L. Pallone, Descending vasa recta pericytes express voltage operated Na+ conductance in the rat. J. Physiol. 567, 445–457 (2005)PubMedCrossRefGoogle Scholar
  73. S. Zhang, H. Dong, L.J. Rubin, J.X. Yuan, Upregulation of Na+/Ca2+ exchanger contributes to the enhanced Ca2+ entry in pulmonary artery smooth muscle cells from patients with idiopathic pulmonary arterial hypertension. Am. J. Physiol. Cell Physiol. 292, C2297–C2305 (2007a)PubMedCrossRefGoogle Scholar
  74. S. Zhang, H.H. Patel, F. Murray, C.V. Remillard, C. Schach, P.A. Thistlethwaite, P.A. Insel, J.X. Yuan, Pulmonary artery smooth muscle cells from normal subjects and IPAH patients show divergent cAMP-mediated effects on TRPC expression and capacitative Ca2+ entry. Am. J. Physiol. Lung Cell. Mol. Physiol. 292, L1202–L1210 (2007b)PubMedCrossRefGoogle Scholar
  75. A. Zulian, S.G. Baryshnikov, C.I. Linde, J.M. Hamlyn, P. Ferrari, V.A. Golovina, Upregulation of Na+/Ca2+ exchanger and TRPC6 contributes to abnormal Ca2+ homeostasis in arterial smooth muscle cells from Milan hypertensive rats. Am. J. Physiol. Heart Circ. Physiol. 299, H624–H633 (2010a)PubMedCrossRefGoogle Scholar
  76. A. Zulian, M.V. Pulina, C.I. Linde, S. Baryshnikov, J.M. Hamlyn, M.P. Blaustein, V.A. Golovina, Digoxin blocks ouabain-induced hypertension by preventing up-regulation of the Na/Ca exchanger-1/TRPC6 Ca2+ signaling pathway. Hypertension 56, e57 (2010b)Google Scholar

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© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Departments of Physiology and MedicineUniversity of Maryland School of MedicineBaltimoreUSA

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