Sodium/Calcium Exchange: Its Physiological Implications

Abstract

The Na+/Ca2+exchanger, an ion transport protein, is expressed in the plasma membrane (PM) of virtually all animal cells. It extrudes Ca2+in parallel with the PM ATP-driven Ca2+pump. As a reversible transporter, it also mediates Ca2+entry in parallel with various ion channels. The energy for net Ca2+transport by the Na+/Ca2+exchanger and its direction depend on the Na+, Ca2+, and K+gradients across the PM, the membrane potential, and the transport stoichiometry. In most cells, three Na+are exchanged for one Ca2+. In vertebrate photoreceptors, some neurons, and certain other cells, K+is transported in the same direction as Ca2+, with a coupling ratio of four Na+to one Ca2+plus one K+. The exchanger kinetics are affected by nontransported Ca2+, Na+, protons, ATP, and diverse other modulators. Five genes that code for the exchangers have been identified in mammals: three in the Na+/Ca2+exchanger family ( NCX1, NCX2, and NCX3) and two in the Na+/Ca2+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 Ca2+concentration; its possible role in cardiac excitation-contraction coupling is controversial. Cellular increases in Na+concentration lead to increases in Ca2+concentration mediated by the Na+/Ca2+exchanger; this is important in the therapeutic action of cardiotonic steroids like digitalis. Similarly, alterations of Na+and Ca2+apparently modulate basolateral K+conductance in some epithelia, signaling in some special sense organs (e.g., photoreceptors and olfactory receptors) and Ca2+-dependent secretion in neurons and in many secretory cells. The juxtaposition of PM and sarco(endo)plasmic reticulum membranes may permit the PM Na+/Ca2+exchanger to regulate sarco(endo)plasmic reticulum Ca2+stores and influence cellular Ca2+signaling.