19 - Na+−Ca2+ Exchange Currents

Abstract

This chapter offers brief information on the current knowledge of Na+-Ca2+ exchange currents. The early studies paved the way for a number of subsequent investigations that have led to molecular cloning and elucidation of the structure of the exchanger molecule itself. This in turn introduced the possibility of studying the relationship between molecular structure and function. The chapter discusses several aspects of Na+-Ca2+ exchanger, including structure, topology, and distribution, phylogeny, isoforms, energetics, methods and problems associated with the measurement, isolation of Na+-Ca2+ exchange current, ionic dependencies, regulation of current, current-voltage relationships and voltage dependence of Na+-Ca2+ exchange current and mechanism, Na+-Ca2+ exchange currents during the cardiac action potential, and excitation-contraction coupling. Isolation of Na+-Ca2+ exchange current includes whole-cell patch-clamp studies, and Na+-Ca2+ exchange current reversal potential. It is mentioned that the generation of phosphatidylinositol-4,5-bisphosphate (PIP2) is an important regulator of Na+-Ca2+ exchange activity in heart. The ease with which heart cells can be patch-clamped, together with the presence of a vigorous exchange activity, clearly explains the fact that most of our information on exchange current comes from this tissue. Na+-Ca2+ exchange currents have been measured in other cell types, including the squid giant axon. Although measurements of exchange current are difficult in many tissues, it is now possible to express Na+-Ca2+ exchangers in frog oocytes. This together with the development of giant excised patches that can be voltage clamped has made studies of the relationship between structure of the exchanger and function much easier. Measurements of both whole-cell currents as well as currents in giant patches have produced evidence in favor of the idea that a consecutive mechanism can explain exchange activity. Most recently, Na+-Ca2+ exchange currents have been proposed as a trigger for SR Ca2+ release under physiological conditions. Thus, in the last 30 years, the study of exchange currents has expanded enormously to provide not only insight into the way that the Na+-Ca2+ exchange controls intracellular Ca2+ at the whole-cell level, but also into the details of the molecular mechanism of the exchange reaction itself.