Pushing and Pulling the Cardiac Sodium/Hydrogen Exchanger

Abstract

See related article, pages 881–890 The strangest animal in Dr Dolittle’s zoo was a Pushmi-pullyu (pronounced push-me-pull-you), a mythical chimera of 2 antelopes, with a head at each end. Sometimes it looked and moved forwards, sometimes backwards. The direction could be coaxed by Dr Dolittle (played originally by Rex Harrison in the Hollywood movie), who spoke to the animal in its own language. A report from the laboratory of Avkiran, published in this issue of Circulation Research ,1 shows that there is something strangely reminiscent of the Pushmi-pullyu in the cardiac sodium–hydrogen exchanger (NHE1), a ubiquitous, dimeric glycoprotein, intimately involved with the regulation of intracellular pH (pHi) (reviewed elsewhere2). In cardiac myocytes, the NHE1 protein product is expressed at the sarcolemma. It is a secondary active transporter expelling one H+ ion in exchange for the entry of one Na+ ion, and its activity is governed acutely by the intracellular H+ ion concentration (ie, pHi). Activity increases steeply when pHi falls from its resting level of ≈7.2. This is why the protein is so effective as a pHi regulator. But why the resemblance to a Pushmi-pullyu? It is becoming apparent that NHE1 in the cardiac cell can be both stimulated and inhibited directly by intracellular signaling cascades. Like Dr Dolittle, these talk to the transporter, and the chorus determines whether cellular H+ extrusion during intracellular acidosis is stimulated or inhibited. It has long been known that the pHi sensitivity of NHE1 can be enhanced through a coupling of the transport protein to surface membrane receptors, operating via endogenous intracellular ligands.2 Many of the pathways involved have been highlighted in other tissues, but, in the cardiac myocyte, typical extracellular receptor agonists that stimulate NHE1 activity are angiotensin II (acting …