Regulation of myocardial Na+/H+ exchanger activity

The Na+/H+ exchanger is a plasma membrane protein, present in the myocardium, which removes intracellular protons and exchanges them with extracellular Na+. The protein comprises an N-terminal, hydrophobic, integral membrane domain that transports the ions and a C-terminal, hydrophilic region that regulates the N-terminal domain. The C-terminal domain has several sub-domains, including one region that binds calmodulin and another that is phosphorylated by protein kinases. The Na+/H+ exchanger is activated by angiotensin, endothelin and alpha1-adrenergic stimulation. These effectors increase phosphorylation of the C-terminal domain by protein kinases, and G proteins have been implicated in this, but their role remains to be defined. It has recently been shown that ischemia and other stimuli lead to an increased expression of the Na+/H+ exchanger in the myocardium. The role of this increased expression in the pathology of ischemia and reperfusion-mediated myocardial damage has yet to be determined. Recent evidence suggests that the Na+/H+ exchanger may play a key role in hypertrophy of the myocardium, and that its activation through G protein-coupled receptors may be important in mediating its effects.