Mechanism by which Liddle's syndrome mutations increase activity of a human epithelial Na+ channel

Peter M. Snyder, Margaret P. Price, Fiona J. McDonald, Christopher M. Adams, Kenneth A. Volk, Bernhardt G. Zeiher, John B. Stokes, Michael J. Welsh

Research output: Contribution to journalArticlepeer-review

Abstract

Liddle's syndrome is an inherited form of hypertension caused by mutations that truncate the C-terminus of human epithelial Na+ channel (hENaC) subunits. Expression of truncated β and γ hENaC subunits increased Na+ current. However, truncation did not alter single-channel conductance or open state probability, suggesting there were more channels in the plasma membrane. Moreover, truncation of the C-terminus of the β subunit increased apical cell-surface expression of hENaC in a renal epithelium. We identified a conserved motif in the C-terminus of all three subunits that, when mutated, reproduced the effect of Liddle's truncations. Further, both truncation of the C-terminus and mutation of the conserved C-terminal motif increased surface expression of chimeric proteins containing the C-terminus of β hENaC. Thus, by deleting a conserved motif, Liddle's mutations increase the number of Na+ channels in the apical membrane, which increases renal Na+ absorption and creates a predisposition to hypertension.

Original languageEnglish (US)
Pages (from-to)969-978
Number of pages10
JournalCell
Volume83
Issue number6
DOIs
StatePublished - Dec 15 1995

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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