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Am J Physiol Renal Physiol (May 20, 2003). doi:10.1152/ajprenal.00071.2003
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Submitted on February 19, 2003
Accepted on May 7, 2003

Epithelial sodium channel (ENaC) mutants causing Liddle syndrome retain their ability to respond to aldosterone and vasopressin

Muriel Auberson1, Nicole Hoffmann-Pochon1, Alain Vandewalle2, Stephan Kellenberger1, and Laurent Schild1*

1 Institut de Pharmacologie & Toxicologie, Universite de Lausanne, Lausanne, Switzerland
2 U478, INSERM, Paris, France

* To whom correspondence should be addressed. E-mail: Laurent.Schild{at}ipharm.unil.ch.

Liddle syndrome is a monogenic form of hypertension caused by mutations in the PY motif of the C-terminus of {beta} and {gamma} ENaC subunits. These mutations lead to retention of active channels at the cell surface. Because of the critical role of this PY motif in the stability of ENaC at the cell surface we have investigated its contribution to the ENaC response to aldosterone and vasopressin. Mutants of the PY motif in {beta} and {gamma} ENaC subunits ({beta}Y618A, {beta}P616L, {beta}R564stop+{gamma}K570stop) were stably expressed by retroviral gene transfer in a renal cortical collecting duct cell line (mpkCCDcl4), and the transepithelial Na+ transport was assessed by measurements of the benzamil-sensitive short-circuit current (Isc). Cells expressing ENaC mutants of the PY motif showed a 5-6 fold higher basal Isc compared to control, and responded to stimulation by aldosterone (10-6 M) or vasopressin (10-9) with a further increase in Isc. The rate of the initial increase in Isc after aldosterone or vasopressin was comparable in cells transduced with ENaC wild type and mutants, but the reversal of the aldosterone and vasopressin effects was slower in cells expressing the ENaC mutants. The conserved sensitivity of ENaC mutants to stimulation by aldosterone and vasopressin together with their prolonged activity at the cell surface likely contributes to the increased Na+ absorption in the distal nephron of patients with Liddle syndrome.




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