A human Na+/H+ antiporter sharing evolutionary origins with bacterial NhaA may be a candidate gene for essential hypertension

Proc Natl Acad Sci U S A. 2007 Nov 20;104(47):18677-81. doi: 10.1073/pnas.0707120104. Epub 2007 Nov 13.

Abstract

Phylogenetic analysis of the cation/proton antiporter superfamily has uncovered a previously unknown clade of genes in metazoan genomes, including two previously uncharacterized human isoforms, NHA1 and NHA2, found in tandem on human chromosome 4. The NHA (sodium hydrogen antiporter) family members share significant sequence similarity with Escherichia coli NhaA, including a conserved double aspartate motif in predicted transmembrane 5. We show that HsNHA2 (Homo sapiens NHA2) resides on the plasma membrane and, in polarized MDCK cells, localizes to the apical domain. Analysis of mouse tissues indicates that NHA2 is ubiquitous. When expressed in the yeast Saccharomyces cerevisiae lacking endogenous cation/proton antiporters and pumps, HsNHA2 can confer tolerance to Li(+) and Na(+) ions but not to K(+). HsNHA2 transformants accumulated less Li(+) than the salt-sensitive host; however, mutagenic replacement of the conserved aspartates abolished all observed phenotypes. Functional complementation by HsNHA2 was insensitive to amiloride, a characteristic inhibitor of plasma membrane sodium hydrogen exchanger isoforms, but was inhibited by phloretin. These are hallmarks of sodium-lithium countertransport activity, a highly heritable trait correlating with hypertension. Our findings raise the possibility that NHA genes may contribute to sodium-lithium countertransport activity and salt homeostasis in humans.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Conserved Sequence
  • Escherichia coli / genetics
  • Escherichia coli / metabolism
  • Escherichia coli Proteins / genetics
  • Escherichia coli Proteins / metabolism*
  • Evolution, Molecular*
  • Gene Expression Regulation
  • Humans
  • Hypertension / genetics
  • Hypertension / metabolism*
  • Molecular Sequence Data
  • Phenotype
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism
  • Sequence Alignment
  • Sodium-Hydrogen Exchangers / chemistry
  • Sodium-Hydrogen Exchangers / classification
  • Sodium-Hydrogen Exchangers / genetics
  • Sodium-Hydrogen Exchangers / metabolism*

Substances

  • Escherichia coli Proteins
  • NhaA protein, E coli
  • Sodium-Hydrogen Exchangers