Sodium‐Calcium exchange: A possible target for drug development

The Na + ‐Ca 2+ exchange system is a carrier‐mediated transport process which couples the transmembrane movement of Ca 2+ ions to the movement of Na + ions in the opposite direction. It functions primarily as a Ca 2+ extrusion process in cardiac cells and is thought to be an important mechanism for altering myocardial contractility through changes in intracellular [Na + ]. We khave investigated the properties of the cardiac Na + ‐Ca 2+ exchange system using a subcellular preparation of membrane vesicles derived from the cardiac sarcolemma. Vesicle studies have been useful in investigating the kinetics of Na + ‐Ca 2+ exchange activity and in establishin the stoichiometry of the exchange process as 3 Na + per Ca 2+ . The kinetec results are most easily interpreted in terms of a model for the Na + ‐Ca 2+ exchange carrier which features two types of cation binding sites: a divalent site for which Ca 2+ and 1‐2 Na + ions compete and a second, monovalent site which binds the third Na + involved in Na + ‐Ca 2+ exchange. Na + ‐Ca 2+ exchange activity in vesicles is stimulated by a variety of agents or treatments, including limited proteolysis, phospholipase treatment, redox reagents, anionic amphiphiles, and intravesicular Ca 2+ , all of which lower the apparent K m for Ca 2+ . The physiological significance of these modes of regulation of exchange activity is at present uncertain. Progress in identifying and purifying the exchange carrier has been hampered by the lack of specific high‐affinity probes that could be used in labelling studies. Indirect estimates of the number of exchange carriers in sarcolemmal vesicles suggest that there are 10‐20 pmol of exchanger per mg of membrane protein and that the exchange system has a maximal turnover of approximately 10 3 sec −1 . Studies are under way in several laboratories to clone a cDNA for the exchange carrier using oocytes of Xenopus laevis as an expression system.