Molecular properties, kinetics and regulation of mammalian Na+/H+ exchangers

Chung Ming Tse, Susan A. Levine, C. H.Chris Yun, Steven R. Brant, Samir Natha, Jacques Pouysségur, Mark Donowitz

Research output: Contribution to journalArticlepeer-review

Abstract

Four mammalian Na+/H+ exchangers (NHE1, NHE2, NHE3 and NHE4) have been cloned. By Northern blot analysis and by immunocytochemistry, NHE1 is the housekeeping isoform Na+/H+ exchanger. NHE2 and NHE3 are epithelial cell-specific with NHE3 having properties of the intestinal and renal brush-border membrane Na+/H+ exchanger. Pharmacologically, these Na+/H+ exchangers exhibit a wide range in amiloride sensitivity with NHE1 and NHE2 being amiloride-sensitive and NHE3 being amiloride-resistant. Kinetically, they exhibit similar Na+ and H+ kinetics. Structurally, all cloned Na+/H+ exchangers have 10-12 membrane-spanning domains and a long cytoplasmic C-terminus. Structure-function studies suggest that the membrane-spanning domains are responsible for catalyzing Na+ and H+ exchange and the C-terminus is responsible for kinase regulation of Na+/H+ exchange. Although all cloned exchangers respond to growth factor and protein kinase regulation, mechanistically, NHE1 is stimulated by a change in the affinity for intracellular H+, and NHE2 and NHE3 are regulated by a change in the Vmax of exchange. Qualitatively, growth factors have only stimulatory effects on NHE1 and NHE2 but can stimulate or inhibit NHE3. In conclusion, a gene family of Na+/H+ exchangers with a diversity in amiloride sensitivity and kinase regulation has been identified. Based on the pharmacological and physiological characteristics of NHE3, it is the Na+/H+ exchanger responsible for Na+ absorption in the brush-border membranes in intestinal and renal epithelial cells.

Original languageEnglish (US)
Pages (from-to)282-300
Number of pages19
JournalCellular Physiology and Biochemistry
Volume4
Issue number5-6
DOIs
StatePublished - Jan 1 1994

Keywords

  • Epithelial Na absorption
  • Gene family
  • Growth factors
  • Kinase regulation
  • Membrane protein
  • Na/H exchanger

ASJC Scopus subject areas

  • Physiology

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