Journal article
Intracellular Sodium Regulates Proteolytic Activation of the Epithelial Sodium Channel
The Journal of biological chemistry, Vol.283(41), pp.27477-27482
10/10/2008
DOI: 10.1074/jbc.M804176200
PMCID: PMC2562069
PMID: 18662987
Abstract
Na
+
transport across epithelia is mediated in part by the
epithelial Na
+
channel ENaC. Previous work indicates that
Na
+
is an important regulator of ENaC, providing a negative
feedback mechanism to maintain Na
+
homeostasis. ENaC is synthesized
as an inactive precursor, which is activated by proteolytic cleavage of the
extracellular domains of the α and γ subunits. Here we found that
Na
+
regulates ENaC in part by altering proteolytic activation of
the channel. When the Na
+
concentration was low, we found that the
majority of ENaC at the cell surface was in the cleaved/active state. As
Na
+
increased, there was a dose-dependent decrease in ENaC cleavage
and, hence, ENaC activity. This Na
+
effect was dependent on
Na
+
permeation; cleavage was increased by the ENaC blocker
amiloride and by a mutation that decreases ENaC activity
(α
H69A
) and was reduced by a mutation that activates ENaC
(β
S520K
). Moreover, the Na
+
ionophore monensin
reversed the effect of the inactivating mutation (α
H69A
) on
ENaC cleavage, suggesting that intracellular Na
+
regulates
cleavage. Na
+
did not alter activity of Nedd4-2, an E3 ubiquitin
ligase that modulates ENaC cleavage, but Na
+
reduced ENaC cleavage
by exogenous trypsin. Our findings support a model in which intracellular
Na
+
regulates cleavage by altering accessibility of ENaC cleavage
sites to proteases and provide a molecular explanation for the earlier
observation that intracellular Na
+
inhibits Na
+
transport via ENaC (Na
+
feedback inhibition).
Details
- Title: Subtitle
- Intracellular Sodium Regulates Proteolytic Activation of the Epithelial Sodium Channel
- Creators
- Kristin K Knight - Departments of Internal Medicine and Molecular Physiology and Biophysics, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242Danielle M Wentzlaff - Departments of Internal Medicine and Molecular Physiology and Biophysics, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242Peter M Snyder - Departments of Internal Medicine and Molecular Physiology and Biophysics, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242
- Resource Type
- Journal article
- Publication Details
- The Journal of biological chemistry, Vol.283(41), pp.27477-27482
- DOI
- 10.1074/jbc.M804176200
- PMID
- 18662987
- PMCID
- PMC2562069
- NLM abbreviation
- J Biol Chem
- ISSN
- 0021-9258
- eISSN
- 1083-351X
- Publisher
- American Society for Biochemistry and Molecular Biology
- Language
- English
- Date published
- 10/10/2008
- Academic Unit
- Molecular Physiology and Biophysics; Cardiovascular Medicine; Medicine Administration; Internal Medicine
- Record Identifier
- 9984025683702771
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