2014 - Keeping it simple, transport mechanism and pH regulation in Na+/H+ exchangers

Icon N1  SURFE²R-technology (custom-built system) publication in Journal of Biological Chemistry (2014)

Călinescu O., Paulino C., Kühlbrandt W., Fendler K.

Journal of Biological Chemistry (2014) 289(19):13168-13176


Na+/H+ exchangers are essential for regulation of intracellular proton and sodium concentrations in all living organisms. We examined and experimentally verified a kinetic model for Na+/H+ exchangers, where a single binding site is alternatively occupied by Na+ or one or two H+ ions. The proposed transport mechanism inherently down-regulates Na+/H+ exchangers at extreme pH, preventing excessive cytoplasmic acidification or alkalinization. As an experimental test system we present the first electrophysiological investigation of an electroneutral Na+/H+ exchanger, NhaP1 from Methanocaldococcus jannaschii (MjNhaP1), a close homologue of the medically important eukaryotic NHE Na+/H+ exchangers. The kinetic model describes the experimentally observed substrate dependences of MjNhaP1, and the transport mechanism explains alkaline down-regulation of MjNhaP1. Because this model also accounts for acidic down-regulation of the electrogenic NhaA Na+/H+ exchanger from Escherichia coli (EcNhaA, shown in a previous publication) we conclude that it applies generally to all Na+/H+ exchangers, electrogenic as well as electroneutral, and elegantly explains their pH regulation. Furthermore, the electrophysiological analysis allows insight into the electrostatic structure of the translocation complex in electroneutral and electrogenic Na+/H+ exchangers.

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