Sodium calcium exchange: Its physiological implications

The Na+/Ca2+ exchanger, an ion transport protein, is expressed in the plasm a 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 med iates 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 tr ansport stoichiometry. In most cells, three Nat are exchanged for one Ca2+. Ln 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 nontransp orted Ca2+, Na+, protons, ATP, and diverse other modulators. Five genes tha t 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 variant s 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 excita tion-contraction coupling is controversial. Cellular increases in Na+ conce ntration lead to increases in Ca2+ concentration mediated by the Na+/Ca2+ e xchanger; this is important in the therapeutic action of cardiotonic steroi ds like digitalis. Similarly, alterations of Na+ and Ca2+ apparently modula te basolateral K+ conductance in some epithelia, signaling in some special sense organs (e.g., photoreceptors and olfactory receptors) and Ca2+-depend ent secretion in neurons and in many secretory cells. The juxtaposition of PM and sarco(endo)plasmic reticulum membranes may permit the PM Na+/Ca2+ ex changer to regulate sarco(endo)plasmic reticulum Ca2+ stores and influence cellular Ca2+ signaling.