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EMBO J
1997 Mar 03;165:899-907. doi: 10.1093/emboj/16.5.899.
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A mutation causing pseudohypoaldosteronism type 1 identifies a conserved glycine that is involved in the gating of the epithelial sodium channel.
Gründer S
,
Firsov D
,
Chang SS
,
Jaeger NF
,
Gautschi I
,
Schild L
,
Lifton RP
,
Rossier BC
.
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Pseudohypoaldosteronism type 1 (PHA-1) is an inherited disease characterized by severe neonatal salt-wasting and caused by mutations in subunits of the amiloride-sensitive epithelial sodium channel (ENaC). A missense mutation (G37S) of the human ENaC beta subunit that causes loss of ENaC function and PHA-1 replaces a glycine that is conserved in the N-terminus of all members of the ENaC gene family. We now report an investigation of the mechanism of channel inactivation by this mutation. Homologous mutations, introduced into alpha, beta or gamma subunits, all significantly reduce macroscopic sodium channel currents recorded in Xenopus laevis oocytes. Quantitative determination of the number of channel molecules present at the cell surface showed no significant differences in surface expression of mutant compared with wild-type channels. Single channel conductances and ion selectivities of the mutant channels were identical to that of wild-type. These results suggest that the decrease in macroscopic Na currents is due to a decrease in channel open probability (P(o)), suggesting that mutations of a conserved glycine in the N-terminus of ENaC subunits change ENaC channel gating, which would explain the disease pathophysiology. Single channel recordings of channels containing the mutant alpha subunit (alphaG95S) directly demonstrate a striking reduction in P(o). We propose that this mutation favors a gating mode characterized by short-open and long-closed times. We suggest that determination of the gating mode of ENaC is a key regulator of channel activity.
Canessa,
Epithelial sodium channel related to proteins involved in neurodegeneration.
1993, Pubmed,
Xenbase
Canessa,
Epithelial sodium channel related to proteins involved in neurodegeneration.
1993,
Pubmed
,
Xenbase
Canessa,
Amiloride-sensitive epithelial Na+ channel is made of three homologous subunits.
1994,
Pubmed
,
Xenbase
Canessa,
Membrane topology of the epithelial sodium channel in intact cells.
1994,
Pubmed
,
Xenbase
Chalfie,
The identification and suppression of inherited neurodegeneration in Caenorhabditis elegans.
1990,
Pubmed
Chalfie,
Degenerin similarities.
1993,
Pubmed
,
Xenbase
Chang,
Mutations in subunits of the epithelial sodium channel cause salt wasting with hyperkalaemic acidosis, pseudohypoaldosteronism type 1.
1996,
Pubmed
Firsov,
Cell surface expression of the epithelial Na channel and a mutant causing Liddle syndrome: a quantitative approach.
1996,
Pubmed
,
Xenbase
Geering,
A role for the beta-subunit in the expression of functional Na+-K+-ATPase in Xenopus oocytes.
1989,
Pubmed
,
Xenbase
Hansson,
Hypertension caused by a truncated epithelial sodium channel gamma subunit: genetic heterogeneity of Liddle syndrome.
1995,
Pubmed
,
Xenbase
Huang,
Gene interactions affecting mechanosensory transduction in Caenorhabditis elegans.
1994,
Pubmed
Kemendy,
Aldosterone alters the open probability of amiloride-blockable sodium channels in A6 epithelia.
1992,
Pubmed
Li,
Alternatively spliced forms of the alpha subunit of the epithelial sodium channel: distinct sites for amiloride binding and channel pore.
1995,
Pubmed
,
Xenbase
McDonald,
Cloning, expression, and tissue distribution of a human amiloride-sensitive Na+ channel.
1994,
Pubmed
,
Xenbase
McDonald,
Cloning and expression of the beta- and gamma-subunits of the human epithelial sodium channel.
1995,
Pubmed
,
Xenbase
Palmer,
Amiloride-sensitive Na channels from the apical membrane of the rat cortical collecting tubule.
1986,
Pubmed
Palmer,
Gating of Na channels in the rat cortical collecting tubule: effects of voltage and membrane stretch.
1996,
Pubmed
Puoti,
The highly selective low-conductance epithelial Na channel of Xenopus laevis A6 kidney cells.
1995,
Pubmed
,
Xenbase
Renard,
Biochemical analysis of the membrane topology of the amiloride-sensitive Na+ channel.
1994,
Pubmed
,
Xenbase
Rossier,
Epithelial sodium channels.
1994,
Pubmed
Schild,
A mutation in the epithelial sodium channel causing Liddle disease increases channel activity in the Xenopus laevis oocyte expression system.
1995,
Pubmed
,
Xenbase
Shimkets,
Liddle's syndrome: heritable human hypertension caused by mutations in the beta subunit of the epithelial sodium channel.
1994,
Pubmed
Snyder,
Membrane topology of the amiloride-sensitive epithelial sodium channel.
1994,
Pubmed
,
Xenbase
Snyder,
Mechanism by which Liddle's syndrome mutations increase activity of a human epithelial Na+ channel.
1995,
Pubmed
,
Xenbase
Strautnieks,
A novel splice-site mutation in the gamma subunit of the epithelial sodium channel gene in three pseudohypoaldosteronism type 1 families.
1996,
Pubmed
Tamura,
Liddle disease caused by a missense mutation of beta subunit of the epithelial sodium channel gene.
1996,
Pubmed
,
Xenbase
Waldmann,
Molecular cloning and functional expression of a novel amiloride-sensitive Na+ channel.
1995,
Pubmed
,
Xenbase
