title: Extracellular Na+ removal attenuates rundown of the epithelial Na+-channel (ENaC) by reducing the rate of channel retrieval.
abstract: Regulation of the epithelial sodium channel (ENaC) is important for the long-term control of arterial blood pressure as evidenced by gain of function mutations of ENaC causing Liddle's syndrome, a rare form of hereditary arterial hypertension. In Xenopus laevis oocytes expressing ENaC a spontaneous decline of ENaC currents over time, so-called rundown, is commonly observed. Mechanisms involved in rundown may be physiologically relevant and may be related to feedback regulation of ENaC by intra- or extracellular Na+. We tested the effect of extracellular Na+ removal on ENaC rundown. Spontaneous rundown of ENaC was largely prevented by extracellular Na+ removal and was partially prevented by primaquine suggesting that it is due to endocytic channel retrieval. Liddle's syndrome mutation caused a reduced rate of rundown, and in oocytes expressing the mutated channel extracellular Na+ removal not only prevented rundown but even increased the ENaC currents (runup). Acute exposure to high extracellular Na+ drastically reduced whole-cell currents and surface expression of wild-type ENaC, while these effects were much smaller in ENaC with Liddle's syndrome mutation consistent with a stabilization of the mutated channel in the plasma membrane. Interestingly, the apparent intracellular Na+ concentration [Na+](i-app) was high (>60 mM) in ENaC-expressing oocytes but rundown was not associated with a further increase in [Na+](i-app). We conclude that the inhibitory effect of extracellular Na+ removal on rundown is due to an inhibition of endocytic ENaC retrieval.
authors.affiliation: Institut für Zelluläre und Molekulare Physiologie, Universität Erlangen-Nürnberg, Waldstrasse 6, 91054 Erlangen, Germany.
authors.forename: Tilmann
authors.initials: T
authors.lastname: Volk
authors.forename: Angelos-Aristeidis
authors.initials: AA
authors.lastname: Konstas
authors.forename: Peter
authors.initials: P
authors.lastname: Bassalaý
authors.forename: Heimo
authors.initials: H
authors.lastname: Ehmke
authors.forename: Christoph
authors.initials: C
authors.lastname: Korbmacher
mesh_terms: D000818:Animals; D053503:Epithelial Sodium Channels; D045604:Extracellular Fluid / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D012964:Sodium / Q000494:pharmacology*; D062687:Sodium Channel Agonists; D015222:Sodium Channels / Q000096:biosynthesis*; D014982:Xenopus laevis
chemical_list: D053503:Epithelial Sodium Channels; D062687:Sodium Channel Agonists; D015222:Sodium Channels; D012964:Sodium