Ionic regulation of the cardiac sodium-calcium exchanger.

The Na+-Ca2+ exchanger (NCX) links transmembrane movements of Ca2+ ions to the reciprocal movement of Na+ ions. It normally functions primarily as a Ca2+ efflux mechanism in excitable tissues such as the heart, but it can also mediate Ca2+ influx under certain conditions. Na+ and Ca2+ ions exert complex regulatory effects on NCX activity. Ca2+ binds to two regulatory sites in the exchanger's central hydrophilic domain, and this interaction is normally essential for activation of exchange activity. High cytosolic Na+ concentrations, however, can induce a constitutive activity that bypasses the need for allosteric Ca2+ activation. Constitutive NCX activity can also be induced by high levels of phosphatidylinositol-4,5-bisphosphate (PIP2) and by mutations affecting the regulatory calcium binding domains. In addition to promoting constitutive activity, high cytosolic Na+ concentrations also induce an inactivated state of the exchanger (Na+-dependent inactivation) that becomes dominant when cytosolic pH and PIP2 levels fall. Na+-dependent inactivation may provide a means of protecting cells from Ca2+ overload due to NCX-mediated Ca2+ influx during ischemia.