Na+/Ca2+ antiport in the mammalian heart

The cardiac Na+/Ca2+ antiporter moves 3 Na+ across the plasma membrane in exchange for a single Ca2+ moving in the opposite direction. It is the principal Ca2+ efflux mechanism in myocardial cells; however, it also contributes to Ca2+ influx under certain conditions. It is particularly abundant in the heart, but is also expressed in other tissues such as smooth and skeletal muscle, the kidney and the brain. The cardiac antiporter itself is a protein of 938 amino acids, with a cleaved NH2-terminal signal sequence, 11 putative transmembrane segments and a large hydrophilic domain of 520 amino acids between the fifth and sixth transmembrane segments. Alternative mRNA splicing mechanisms generate tissue-specific isoforms in a limited region within the hydrophilic domain. Most of the hydrophilic domain can be deleted without altering the kinetics of the transport reaction; the regulatory properties of the antiporter are markedly affected by this deletion however. Two different modes of regulation of antiport activity have been characterized and appear to involve two different inactive states of the carrier. The first is promoted by the presence of cytosolic Na+ in the absence of ATP and the second is promoted by the absence of cytosolic Ca2+. ATP-dependent regulation of antiport activity may involve interactions with the cellular cytoskeleton, since the effects of ATP depletion can be mimicked by cytochalasin D. Ca(2+)-dependent regulation of antiport activity appears to involve the interaction of cytosolic Ca2+ with two acidic amino acid sequences within a limited region of the hydrophilic domain.