The Na+/H+ exchanger: an update on structure, regulation and cardiac physiology.

Most mammalian cells maintain a physiological cytoplasmic pH of approximately 7.2 despite the prediction of a more acidic internal pH on the basis of thermodynamic and metabolic considerations. If the transmembrane gradient of hydrogen ions were determined solely by a hydrogen ion leak pathway in the presence of a membrane potential of -60 mV, then the cytoplasmic pH would be about 6.2, that is one pH unit more acidic than the extracellular pH. Besides membrane potential, metabolic conditions can contribute an intracellular acid load. This includes production of CO2 in the cell and subsequent conversion to carbonic acid, and metabolic reactions producing other acids. Since there are many conditions, physiological and pathological, which tend to shift the metabolic acid balance, regulatory mechanisms need to be in place to maintain intracellular pH in the face of acidic or alkaline challenges. It is also necessary to change intracellular pH to support changes in the growth or functional state of the cell [1-3]. This is achieved by the interplay of several different mechanisms, including bicarbonatetransporting carriers and Na+/H+ exchange, the relative contributions of which vary among the different cell types [4]. The Na+/H+ exchanger is a universal pathway employed by essentially all eukaryotic cells to regulate intracellular pH [5]. Na+/H+ exchange activity is widely expressed in the animal and plant kingdoms in virtually all cell types. As implied by the name, the exchanger transports Na+ and HI ions in opposite directions across the bilayer membrane. The direction of exchange is governed solely by the two ions' gradients and requires no additional metabolic energy. In higher organisms such as mammals, the free energy in the inward Na+ gradient is greater and therefore powers the HI movement out of the cell against its