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Sodium self-inhibition of human epithelial sodium channel: selectivity and affinity of the extracellular sodium sensing site

Sodium self-inhibition of human epithelial sodium channel: selectivity and affinity of the... The epithelial Na + channel (ENaC) is present in the apical membrane of "tight" epithelia in the distal nephron, distal colon, and airways. Its activity controls the rate of transepithelial sodium transport. Among other regulatory factors, ENaC activity is controlled by the concentration of extracellular Na + , a phenomenon named self-inhibition. The molecular mechanism by which extracellular Na + concentration is detected is not known. To investigate the properties of the extracellular Na + sensing site, we studied the effects of extracellular cations on steady-state amiloride-sensitive outward currents in Na + -loaded oocytes expressing human ENaC and compared them with self-inhibition of inward current after fast solution changes. About half of the inhibition of outward Na + currents was due to self-inhibition itself and the rest might be attributed to conduction site saturation. Self-inhibition by extracellular Li + was similar to that of Na + except for slightly slower kinetics. Ionic selectivity of the inhibition for steady-state outward current was Na + ≥ Li + > K + . We estimated an apparent inhibitory constant ( K I ) of ∼40 mM for extracellular Na + and Li + and found no evidence for a voltage dependence of the K I . Protease treatment induced the expected increase of the amiloride-sensitive current measured in high-Na + concentrations which was due, at least in part, to abolition of self-inhibition. These results demonstrate that both self-inhibition and saturation play a significant role in the inhibition of ENaC by extracellular Na + and that Na + and Li + interact in a similar way with the extracellular cation sensing site. ion channel gating; sodium binding site; protease Address for reprint requests and other correspondence: J.-D. Horisberger, Département de Pharmacologie et de Toxicologie, Bugnon 27, CH-1005 Lausanne, Switzerland (e-mail: jean-daniel.horisberger@unil.ch ) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png AJP - Renal Physiology The American Physiological Society

Sodium self-inhibition of human epithelial sodium channel: selectivity and affinity of the extracellular sodium sensing site

Bize, Vincent; Horisberger, Jean-Daniel
AJP - Renal Physiology , Volume 293 (4): F1137 – Oct 1, 2007
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Publisher
The American Physiological Society
Copyright
Copyright © 2011 the American Physiological Society
ISSN
0363-6127
eISSN
1522-1466
DOI
10.1152/ajprenal.00100.2007
pmid
17670907
Publisher site
See Article on Publisher Site

Abstract

The epithelial Na + channel (ENaC) is present in the apical membrane of "tight" epithelia in the distal nephron, distal colon, and airways. Its activity controls the rate of transepithelial sodium transport. Among other regulatory factors, ENaC activity is controlled by the concentration of extracellular Na + , a phenomenon named self-inhibition. The molecular mechanism by which extracellular Na + concentration is detected is not known. To investigate the properties of the extracellular Na + sensing site, we studied the effects of extracellular cations on steady-state amiloride-sensitive outward currents in Na + -loaded oocytes expressing human ENaC and compared them with self-inhibition of inward current after fast solution changes. About half of the inhibition of outward Na + currents was due to self-inhibition itself and the rest might be attributed to conduction site saturation. Self-inhibition by extracellular Li + was similar to that of Na + except for slightly slower kinetics. Ionic selectivity of the inhibition for steady-state outward current was Na + ≥ Li + > K + . We estimated an apparent inhibitory constant ( K I ) of ∼40 mM for extracellular Na + and Li + and found no evidence for a voltage dependence of the K I . Protease treatment induced the expected increase of the amiloride-sensitive current measured in high-Na + concentrations which was due, at least in part, to abolition of self-inhibition. These results demonstrate that both self-inhibition and saturation play a significant role in the inhibition of ENaC by extracellular Na + and that Na + and Li + interact in a similar way with the extracellular cation sensing site. ion channel gating; sodium binding site; protease Address for reprint requests and other correspondence: J.-D. Horisberger, Département de Pharmacologie et de Toxicologie, Bugnon 27, CH-1005 Lausanne, Switzerland (e-mail: jean-daniel.horisberger@unil.ch )

Journal

AJP - Renal Physiology – The American Physiological Society

Published: Oct 1, 2007

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