MUTATIONS CAUSING LIDDLE-SYNDROME REDUCE SODIUM-DEPENDENT DOWN-REGULATION OF THE EPITHELIAL SODIUM-CHANNEL IN THE XENOPUS OOCYTE EXPRESSIONSYSTEM

Liddle syndrome is an autosomal dominant form of hypertension resultin g from deletion or missense mutations of a PPPxY motif in the cytoplas mic COOH terminus of either the beta or gamma subunit of the epithelia l Na channel (ENaC). These mutations lead to increased channel activit y, In this study we show that wild-type ENaC is downregulated by intra cellular Na+, and that Liddle mutants decrease the channel sensitivity to inhibition by intracellular Na+. This event results at high intrac ellular Na+ activity in 1.2-2.4-fold higher cell surface expression, a nd 2.8-3.5-fold higher average current per channel in Liddle mutants c ompared with the wild type. In addition, we show that a rapid increase in the intracellular Na+ activity induced downregulation of the activ ity of wild-type ENaC, but not Liddle mutants, on a time scale of minu tes, which was directly correlated to the magnitude of the Na+ influx into the oocytes, Feedback inhibition of ENaC by intracellular Na+ lik ely represents an important cellular mechanism for controlling Na+ rea bsorption in the distal nephron that has important implications for th e pathogenesis of hypertension.