Molecular regulation of the cardiac sodium-calcium exchanger

The cardiac Na+-Ca2+ exchanger plays an important role in controlling cardiac contractility by regulating intracellular Ca2+ homeostasis. Exchanger activity is modulated by a variety of factors. Intracellular Ca2+ ions, which bind to a high affinity Ca2+ binding site, stimulate activity by removing the Na+-dependent inactivation of the ion transport process. Redox reagents have also been shown to enhance Na+-Ca2+ exchange activity. Experiments using a cysteine-less mutant exchanger showed that the effect does not depend on the rearrangement of an intracellular disulfide bond, as previously postulated. The stimulatory effect of ATP on the exchanger activity is mediated by PIP2 and is largely due to the removal of the Na+-dependent inactivation. The endogenous XIP region in the intracellular loop of the Na+-Ca2+ exchanger plays an important role in this inactivation process. PIP2 has been shown to bind XIP peptide with high affinity and specificity.