ENaC and its regulatory proteins as drug targets for blood pressure control.

Details

Serval ID
serval:BIB_1D8095F56770
Type
Article: article from journal or magazin.
Publication sub-type
Review (review): journal as complete as possible of one specific subject, written based on exhaustive analyses from published work.
Collection
Publications
Institution
Title
ENaC and its regulatory proteins as drug targets for blood pressure control.
Journal
Current Drug Targets
Author(s)
Rotin D., Schild L.
ISSN
1873-5592[electronic]
Publication state
Published
Issued date
2008
Volume
9
Number
8
Pages
709-716
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't ; Review
Abstract
Hypertension is a serious medical problem affecting millions of people worldwide. A key protein regulating blood pressure is the Epithelial Na(+) Channel (ENaC). In accord, loss of function mutations in ENaC (PHA1) cause hypotension, whereas gain of function mutations (Liddle syndrome) result in hypertension. The region mutated in Liddle syndrome, called the PY motif (L/PPxY), serves as a binding site for the ubiquitin ligase Nedd4-2, a C2-WW-Hect E3 ubiquitin ligase. Nedd4-2 binds the ENaC-PY motif via it WW domains, ubiquitylates the channel and targets it for endocytosis, a process impaired in Liddle syndrome due to poor binding of the channel to Nedd4-2. This leads to accumulation of active channels at the cell surface and increased Na(+) (and fluid) absorption in the distal nephron, resulting in elevated blood volume and blood pressure. Compounds that destabilize cell surface ENaC, or enhance Nedd4-2 activity in the kidney, could potentially serve as drug targets for hypertension. In addition, recent discoveries of regulation of activation of ENaC by proteases such as furin, prostasin and elastase, which cleave the extracellular domain of this channel leading to it activation, as well as the identification of inhibitors that block the activity of these proteases, provide further avenues for drug targeting of ENaC and the control of blood pressure.
Keywords
Animals, Binding Sites, Blood Pressure/drug effects, Drug Delivery Systems, Epithelial Sodium Channel/drug effects, Epithelial Sodium Channel/metabolism, Humans, Hypertension/drug therapy, Hypertension/genetics, Peptide Hydrolases/drug effects, Peptide Hydrolases/metabolism, Sodium/metabolism, Ubiquitin-Protein Ligases/drug effects, Ubiquitin-Protein Ligases/metabolism
Pubmed
Web of science
Create date
30/10/2009 12:33
Last modification date
20/08/2019 12:53
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