Journal article
Extracellular Protons Regulate Human ENaC by Modulating Na+ Self-inhibition
The Journal of biological chemistry, Vol.284(2), pp.792-798
01/09/2009
DOI: 10.1074/jbc.M806954200
PMCID: PMC2613628
PMID: 18990692
Abstract
The epithelial Na
+
channel, ENaC, is exposed to a wide range of
proton concentrations in the kidney, lung, and sweat duct. We, therefore,
tested whether pH alters ENaC activity. In
Xenopus
oocytes expressing
human α-, β-, and γENaC, amiloride-sensitive current was
altered by protons in the physiologically relevant range (pH 8.5-6.0).
Compared with pH 7.4, acidic pH increased ENaC current, whereas alkaline pH
decreased current (pH
50
= 7.2). Acidic pH also increased ENaC
current in H441 epithelia and in human primary airway epithelia. In contrast
to human ENaC, pH did not alter rat ENaC current, indicating that there are
species differences in ENaC regulation by protons. This resulted predominantly
from species differences in γENaC. Maneuvers that lock ENaC in a high
open-probability state (“DEG” mutation, proteolytic cleavage)
abolished the effect of pH on human ENaC, indicating that protons alter ENaC
current by modulating channel gating. Previous work showed that ENaC gating is
regulated in part by extracellular Na
+
(“Na
+
self-inhibition”). Based on several observations, we conclude that
protons regulate ENaC by altering Na
+
self-inhibition. First,
protons reduced Na
+
self-inhibition in a dose-dependent manner.
Second, ENaC regulation by pH was abolished by removing Na
+
from
the extracellular bathing solution. Third, mutations that alter Na
+
self-inhibition produced corresponding changes in ENaC regulation by pH.
Together, the data support a model in which protons modulate ENaC gating by
relieving Na
+
self-inhibition. We speculate that this may be an
important mechanism to facilitate epithelial Na
+
transport under
conditions of acidosis.
Details
- Title: Subtitle
- Extracellular Protons Regulate Human ENaC by Modulating Na+ Self-inhibition
- Creators
- Daniel M Collier - 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.284(2), pp.792-798
- DOI
- 10.1074/jbc.M806954200
- PMID
- 18990692
- PMCID
- PMC2613628
- NLM abbreviation
- J Biol Chem
- ISSN
- 0021-9258
- eISSN
- 1083-351X
- Publisher
- American Society for Biochemistry and Molecular Biology
- Language
- English
- Date published
- 01/09/2009
- Academic Unit
- Molecular Physiology and Biophysics; Cardiovascular Medicine; Medicine Administration; Internal Medicine
- Record Identifier
- 9984025585502771
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