Keeping It Simple, Transport Mechanism and pH Regulation in Na (+)/H (+) Exchangers

Calinescu, O., Batista Paulino, C., Kuehlbrandt, W. & Fendler, K., 9-May-2014, In : The Journal of Biological Chemistry. 289, 19, p. 13168-13176 9 p.

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Background: Na+/H+ exchangers have a pronounced pH dependence previously explained by pH sensors. Results: Electrophysiological investigation of NhaP1 from Methanocaldococcus jannaschii (MjNhaP1), a prototype of electroneutral Na+/H+ exchangers, allowed its kinetic characterization. Conclusion: The pH dependence of Na+/H+ exchangers is an inherent property of their transport mechanism. Significance: The proposed mechanism of transport and pH regulation applies to all Na+/H+ exchangers.

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.
Original languageEnglish
Pages (from-to)13168-13176
Number of pages9
JournalThe Journal of Biological Chemistry
Issue number19
Publication statusPublished - 9-May-2014
Externally publishedYes


  • Archaea, Electrophysiology, Membrane transport, pH regulation, sodium proton exchange, EcNhaA, MjNhaP1, cation proton antiporter, solid supported membrane

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