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Epithelial Na⁺ channel mutants causing Liddle's syndrome retain ability to respond to aldosterone and vasopressin

¹Institut de Pharmacologie et Toxicologie, Université de Lausanne, CH-1005 Lausanne, Switzerland; and ²Institut National de la Santé et de la Recherche Médicale, Unité 478, Faculté de Médecine Xavier Bichat, 75870 Paris Cedex 18, France

Submitted 19 February 2003 ; accepted in final form 7 May 2003

Liddle's syndrome is a monogenic form of hypertension caused by mutations in the PY motif of the COOH terminus of - and -epithelial Na⁺ channel (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 ENaCs at the cell surface, we have investigated its contribution to the ENaC response to aldosterone and vasopressin. Mutants of the PY motif in - and -ENaC subunits (-Y618A, -P616L, -R564stop, and -K570stop) were stably expressed by retroviral gene transfer in a renal cortical collecting duct cell line (mpkCCD_cl4), and transepithelial Na⁺ transport was assessed by measurements of the benzamil-sensitive short-circuit current (I_sc). Cells that express ENaC mutants of the PY motif showed a five- to sixfold higher basal I_sc compared with control cells and responded to stimulation by aldosterone (10^-6 M) or vasopressin (10^-9 M) with a further increase in I_sc. The rates of the initial increases in I_sc after aldosterone or vasopressin stimulation were comparable in cells transduced with wild-type and mutant ENaCs, but reversal of the effects of aldosterone and vasopressin was slower in cells that expressed the ENaC mutants. The conserved sensitivity of ENaC mutants to stimulation by aldosterone and vasopressin together with the prolonged activity at the cell surface likely contribute to the increased Na⁺ absorption in the distal nephron of patients with Liddle's syndrome.

collecting duct; PY motif; hypertension

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