Structural and functional insights into the cardiac Na⁺/H⁺ exchanger.

ABSTRACT

The NHE1 isoform of the Na(+)/H(+) exchanger is present in the plasma membrane of the mammalian myocardium where it functions to regulate intracellular pH by exchanging one external Na(+) for an internal proton. The protein is involved in myocardial ischemia/reperfusion damage and in heart hypertrophy. Topology models and experimental evidence suggest that of the 815 amino acids of the protein, approximately 500 are embedded or closely associated with the lipid bilayer while the balance form a cytosolic, regulatory carboxyl-terminal tail. The precise structure of NHE1 is not known although that of an Escherichia coli homolog, NhaA, has been determined. The structures of fragments of the NHE1 membrane domain have been examined by nuclear magnetic resonance. Several transmembrane segments have a general structure of an extended central region flanked by helical segments. The extended regions often contain amino acids that are important in protein function and possibly in cation coordination and transport. The E. coli Na(+)/H(+) exchanger NhaA has a novel fold consisting in part of two helical transmembrane segments with interrupted regions crossing amid the lipid bilayer. The similarity between the crystal structure of NhaA and partial structures of NHE1 suggests that there may be similarities in the mechanism of Na(+)/H(+) exchange. This article is part of a Special Issue entitled "Na(+) Regulation in Cardiac Myocytes".