| ENaC and its regulatory proteins as drug targets for blood pressure control. | |
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MedLine Citation:
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PMID: 18691017 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Daniela Rotin; Laurent Schild |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't; Review |
Journal Detail:
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Title: Current drug targets Volume: 9 ISSN: 1873-5592 ISO Abbreviation: Curr Drug Targets Publication Date: 2008 Aug |
Date Detail:
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Created Date: 2008-08-11 Completed Date: 2008-10-16 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 100960531 Medline TA: Curr Drug Targets Country: Netherlands |
Other Details:
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Languages: eng Pagination: 709-16 Citation Subset: IM |
Affiliation:
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Program in Cell Biology, The Hospital for Sick Children, TMDT-MaRS, Rm 11-305, 101 College St., Toronto, Ont., Canada. drotin@sickkids.ca |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Binding Sites Blood Pressure / drug effects Drug Delivery Systems* Endosomal Sorting Complexes Required for Transport Epithelial Sodium Channel / drug effects*, metabolism Humans Hypertension / drug therapy*, genetics, metabolism Peptide Hydrolases / drug effects, metabolism Sodium / metabolism Ubiquitin-Protein Ligases / drug effects, metabolism |
| Chemical | |
Reg. No./Substance:
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0/Endosomal Sorting Complexes Required for Transport; 0/Epithelial Sodium Channel; 7440-23-5/Sodium; EC 3.4.-/Peptide Hydrolases; EC 6.3.2.19/Nedd4 ubiquitin protein ligases; EC 6.3.2.19/Ubiquitin-Protein Ligases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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