Sodium/Calcium Exchange: Its Physiological Implications

Departments of Physiology and Medicine and the Center for Vascular Biology and Hypertension, University of Maryland School of Medicine, and Department of Molecular Biology and Biophysics, The Medical Biotechnology Center of the Maryland Biotechnology Institute, Baltimore, Maryland Blaustein, Mordecai P. and W. Jonathan Lederer. Sodium/Calcium Exchange: Its Physiological Implications. Physiol. Rev. 79: 763-854, 1999. The Na + /Ca 2+ exchanger, an ion transport protein, is expressed in the plasma membrane (PM) of virtually all animal cells. It extrudes Ca 2+ in parallel with the PM ATP-driven Ca 2+ pump. As a reversible transporter, it also mediates Ca 2+ entry in parallel with various ion channels. The energy for net Ca 2+ transport by the Na + /Ca 2+ exchanger and its direction depend on the Na + , Ca 2+ , and K + gradients across the PM, the membrane potential, and the transport stoichiometry. In most cells, three Na + are exchanged for one Ca 2+ . In vertebrate photoreceptors, some neurons, and certain other cells, K + is transported in the same direction as Ca 2+ , with a coupling ratio of four Na + to one Ca 2+ plus one K + . The exchanger kinetics are affected by nontransported Ca 2+ , Na + , protons, ATP, and diverse other modulators. Five genes that code for the exchangers have been identified in mammals: three in the Na + /Ca 2+ exchanger family ( NCX1 , NCX2 , and NCX3 ) and two in the Na + /Ca 2+ plus K + family ( NCKX1 and NCKX2 ). Genes homologous to NCX1 have been identified in frog, squid, lobster, and Drosophila . In mammals, alternatively spliced variants of NCX1 have been identified; dominant expression of these variants is cell type specific, which suggests that the variations are involved in targeting and/or functional differences. In cardiac myocytes, and probably other cell types, the exchanger serves a housekeeping role by maintaining a low intracellular Ca 2+ concentration; its possible role in cardiac excitation-contraction coupling is controversial. Cellular increases in Na + concentration lead to increases in Ca 2+ concentration mediated by the Na + /Ca 2+ exchanger; this is important in the therapeutic action of cardiotonic steroids like digitalis. Similarly, alterations of Na + and Ca 2+ apparently modulate basolateral K + conductance in some epithelia, signaling in some special sense organs (e.g., photoreceptors and olfactory receptors) and Ca 2+ -dependent secretion in neurons and in many secretory cells. The juxtaposition of