Journal article
Regulation of Epithelial Sodium Channel Trafficking by Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9)
The Journal of biological chemistry, Vol.287(23), pp.19266-19274
06/01/2012
DOI: 10.1074/jbc.M112.363382
PMCID: PMC3365958
PMID: 22493497
Abstract
Background:
The epithelial Na
+
channel ENaC functions as a pathway for Na
+
absorption across epithelia.
Results:
PCSK9 reduced ENaC expression at the cell surface by enhancing its proteasomal degradation.
Conclusion:
PCSK9 inhibits ENaC-mediated Na
+
absorption.
Significance:
These findings provide new insights into mechanisms that regulate Na
+
homeostasis and blood pressure.
The epithelial Na
+
channel (ENaC) is critical for Na
+
homeostasis and blood pressure control. Defects in its regulation cause inherited forms of hypertension and hypotension. Previous work found that ENaC gating is regulated by proteases through cleavage of the extracellular domains of the α and γ subunits. Here we tested the hypothesis that ENaC is regulated by proprotein convertase subtilisin/kexin type 9 (PCSK9), a protease that modulates the risk of cardiovascular disease. PCSK9 reduced ENaC current in
Xenopus
oocytes and in epithelia. This occurred through a decrease in ENaC protein at the cell surface and in the total cellular pool, an effect that did not require the catalytic activity of PCSK9. PCSK9 interacted with all three ENaC subunits and decreased their trafficking to the cell surface by increasing proteasomal degradation. In contrast to its previously reported effects on the LDL receptor, PCSK9 did not alter ENaC endocytosis or degradation of the pool of ENaC at the cell surface. These results support a role for PCSK9 in the regulation of ENaC trafficking in the biosynthetic pathway, likely by increasing endoplasmic reticulum-associated degradation. By reducing ENaC channel number, PCSK9 could modulate epithelial Na
+
absorption, a major contributor to blood pressure control.
Details
- Title: Subtitle
- Regulation of Epithelial Sodium Channel Trafficking by Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9)
- Creators
- Vikas Sharotri - From the Departments of Internal Medicine and Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242Daniel M Collier - From the Departments of Internal Medicine and Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242Diane R Olson - From the Departments of Internal Medicine and Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242Ruifeng Zhou - From the Departments of Internal Medicine and Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242Peter M Snyder - From the Departments of Internal Medicine and Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242
- Resource Type
- Journal article
- Publication Details
- The Journal of biological chemistry, Vol.287(23), pp.19266-19274
- DOI
- 10.1074/jbc.M112.363382
- PMID
- 22493497
- PMCID
- PMC3365958
- NLM abbreviation
- J Biol Chem
- ISSN
- 0021-9258
- eISSN
- 1083-351X
- Publisher
- American Society for Biochemistry and Molecular Biology; 9650 Rockville Pike, Bethesda, MD 20814, U.S.A
- Grant note
- HL058812 / National Institutes of Health
- Alternative title
- PCSK9 Regulates ENaC Trafficking
- Language
- English
- Date published
- 06/01/2012
- Academic Unit
- Molecular Physiology and Biophysics; Cardiovascular Medicine; Medicine Administration; Internal Medicine
- Record Identifier
- 9984025403602771
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