Mechanism by which Liddle's syndrome mutations increase activity of a human epithelial Na+ channel.
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 beta and gamma 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 beta 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 beta 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.
Howard Hughes Medical Institute, University of Iowa College of Medicine Iowa City 52242, USA.
P M
PM
Snyder
M P
MP
Price
F J
FJ
McDonald
C M
CM
Adams
K A
KA
Volk
B G
BG
Zeiher
J B
JB
Stokes
M J
MJ
Welsh
D000584:Amiloride / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D016384:Consensus Sequence; D004285:Dogs; D004553:Electric Conductivity; D053503:Epithelial Sodium Channels; D004848:Epithelium; D016368:Frameshift Mutation; D006801:Humans; D006973:Hypertension / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D015640:Ion Channel Gating / Q000187:drug effects; D007668:Kidney / Q000166:cytology / Q000378:metabolism / Q000503:physiopathology; D008969:Molecular Sequence Data; D009865:Oocytes; D018408:Patch-Clamp Techniques; D017384:Sequence Deletion / Q000235:genetics*; D015222:Sodium Channels / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D013577:Syndrome; D014981:Xenopus
D053503:Epithelial Sodium Channels; D015222:Sodium Channels; D000584:Amiloride