Na+/H+ exchangers. Molecular diversity and relevance to heart.

During the last several years, significant advances have been made in our understanding of the molecular, cellular, and physiological diversity of mammalian Na+/H+ exchangers. This transporter forms a multigene family of at least six members (NHE1-NHE6) that share approximately 20-60% amino acid identity. NHE1 is the most predominant isoform expressed in heart and it contributes significantly to myocardial pHi homeostasis, which is important for maintaining contractility. However, hyperactivation of NHE1 during episodes of cardiac ischemia and reperfusion disrupts the intracellular ion balance, leading to cardiac dysfunction and damage in several animal models, but which can be prevented by pharmacological antagonists of NHE1. Molecular studies have indicated that the predicted transmembrane segments M4 and M9 contain several residues involved in drug sensitivity. Molecular dissection of the drug binding region should facilitate the rational design of more potent and isoform-specific drugs that may provide therapeutic benefit in the prevention of cardiac ischemia and reperfusion injuries.