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Voltage‐dependent gating underlies the PHA1 phenotype caused by mutation of a conserved HG motif in ENaC
Author(s) -
Kucher Volodymyr,
Boiko Nina,
Pochynyuk Oleh,
Stockand James D.
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.606.19
Subject(s) - epithelial sodium channel , gating , pseudohypoaldosteronism , depolarization , chemistry , mutant , medicine , endocrinology , transmembrane domain , intracellular , hyperpolarization (physics) , loss function , microbiology and biotechnology , biophysics , phenotype , biology , biochemistry , gene , stereochemistry , sodium , nuclear magnetic resonance spectroscopy , organic chemistry
Autosomal recessive pseudohypoaldosteronism type 1 (PHA1) is caused by loss of ENaC function leading to inappropriate renal salt wasting. ENaC is a member of the ENaC/Deg superfamily. All members of this superfamily contain a conserved HG motif in their NH 2 ‐terminus. Mutation of the Gly in this motif decreases ENaC activity causing PHA1 in humans. Here, we tested the role of the conserved HG motif to ENaC function. Targeted substitution of either H or G dramatically decreases ENaC P o by causing marked voltage‐dependent gating with P o increasing at hyperpolarizing potentials but being lower at all potentials compared to wild type channels. Mutant ENaC has transient activation and deactivation, not present in wild type channels, associated with hyperpolarization and depolarization. We recently reported that targeted substitution of a conserved Trp at the base of TM1 in ENaC unmasks a similar voltage‐sensitivity associated with decreases in P o , and activation at hyperpolarizing potentials. M 2 proton channels gate through formation and breaking of a ring‐like structure beneath the intracellular mouth of the channel pore dependent on transient interaction between a transmembrane Trp and cytosolic His residue. Interrupting such interaction between Trp‐His may underlie the abnormal voltage‐sensitive gating reported here for PHA1 mutations of ENaC.