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A High Throughput Screen Identifies Chemical Modulators of the Laminin-Induced Clustering of Dystroglycan and Aquaporin-4 in Primary Astrocytes
BACKGROUND: Aquaporin-4 (AQP4) constitutes the principal water channel in the brain and is clusteredat the perivascular astrocyte endfeet. This specific distribution of AQP4 plays a major role in maintaining water homeostasis in the brain. A growing body of evidence points to a role ofthe dystroglyc...
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Formato: | Texto |
Lenguaje: | English |
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Public Library of Science
2011
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3049781/ https://www.ncbi.nlm.nih.gov/pubmed/21408176 http://dx.doi.org/10.1371/journal.pone.0017559 |
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author | Noël, Geoffroy Stevenson, Sarah Moukhles, Hakima |
author_facet | Noël, Geoffroy Stevenson, Sarah Moukhles, Hakima |
author_sort | Noël, Geoffroy |
collection | PubMed |
description | BACKGROUND: Aquaporin-4 (AQP4) constitutes the principal water channel in the brain and is clusteredat the perivascular astrocyte endfeet. This specific distribution of AQP4 plays a major role in maintaining water homeostasis in the brain. A growing body of evidence points to a role ofthe dystroglycan complex and its interaction with perivascular laminin in the clusteringof AQP4 atperivascular astrocyte endfeet. Indeed, mice lacking components of this complex or in which laminin-dystroglycan interaction is disrupted show a delayed onset of brain edema due to a redistribution of AQP4 away from astrocyte endfeet. It is therefore important to identify inhibitory drugs of laminin-dependent AQP4 clustering which may prevent or reduce brain edema. METHODOLGY/PRINCIPAL FINDINGS: In the present study we used primary rat astrocyte cultures toscreen a library of >3,500 chemicals and identified 6 drugs that inhibit the laminin-induced clustering of dystroglycan and AQP4. Detailed analysis of the inhibitory drug, chloranil, revealed that its inhibition of the clustering is due to the metalloproteinase-2-mediated ß-dystroglycan shedding and subsequent loss of laminin interaction with dystroglycan. Furthermore, chemical variants of chloranil induced a similar effect on ß-dystroglycan and this was prevented by the antioxidant N-acetylcysteine. CONCLUSION/SIGNIFICANCE: These findings reveal the mechanism of action of chloranil in preventing the laminin-induced clustering of dystroglycan and AQP4 and validate the use of high-throughput screening as a tool to identify drugs that modulate AQP4 clustering and that could be tested in models of brain edema. |
format | Text |
id | pubmed-3049781 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-30497812011-03-15 A High Throughput Screen Identifies Chemical Modulators of the Laminin-Induced Clustering of Dystroglycan and Aquaporin-4 in Primary Astrocytes Noël, Geoffroy Stevenson, Sarah Moukhles, Hakima PLoS One Research Article BACKGROUND: Aquaporin-4 (AQP4) constitutes the principal water channel in the brain and is clusteredat the perivascular astrocyte endfeet. This specific distribution of AQP4 plays a major role in maintaining water homeostasis in the brain. A growing body of evidence points to a role ofthe dystroglycan complex and its interaction with perivascular laminin in the clusteringof AQP4 atperivascular astrocyte endfeet. Indeed, mice lacking components of this complex or in which laminin-dystroglycan interaction is disrupted show a delayed onset of brain edema due to a redistribution of AQP4 away from astrocyte endfeet. It is therefore important to identify inhibitory drugs of laminin-dependent AQP4 clustering which may prevent or reduce brain edema. METHODOLGY/PRINCIPAL FINDINGS: In the present study we used primary rat astrocyte cultures toscreen a library of >3,500 chemicals and identified 6 drugs that inhibit the laminin-induced clustering of dystroglycan and AQP4. Detailed analysis of the inhibitory drug, chloranil, revealed that its inhibition of the clustering is due to the metalloproteinase-2-mediated ß-dystroglycan shedding and subsequent loss of laminin interaction with dystroglycan. Furthermore, chemical variants of chloranil induced a similar effect on ß-dystroglycan and this was prevented by the antioxidant N-acetylcysteine. CONCLUSION/SIGNIFICANCE: These findings reveal the mechanism of action of chloranil in preventing the laminin-induced clustering of dystroglycan and AQP4 and validate the use of high-throughput screening as a tool to identify drugs that modulate AQP4 clustering and that could be tested in models of brain edema. Public Library of Science 2011-03-07 /pmc/articles/PMC3049781/ /pubmed/21408176 http://dx.doi.org/10.1371/journal.pone.0017559 Text en Noël et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Noël, Geoffroy Stevenson, Sarah Moukhles, Hakima A High Throughput Screen Identifies Chemical Modulators of the Laminin-Induced Clustering of Dystroglycan and Aquaporin-4 in Primary Astrocytes |
title | A High Throughput Screen Identifies Chemical Modulators of the Laminin-Induced Clustering of Dystroglycan and Aquaporin-4 in Primary Astrocytes |
title_full | A High Throughput Screen Identifies Chemical Modulators of the Laminin-Induced Clustering of Dystroglycan and Aquaporin-4 in Primary Astrocytes |
title_fullStr | A High Throughput Screen Identifies Chemical Modulators of the Laminin-Induced Clustering of Dystroglycan and Aquaporin-4 in Primary Astrocytes |
title_full_unstemmed | A High Throughput Screen Identifies Chemical Modulators of the Laminin-Induced Clustering of Dystroglycan and Aquaporin-4 in Primary Astrocytes |
title_short | A High Throughput Screen Identifies Chemical Modulators of the Laminin-Induced Clustering of Dystroglycan and Aquaporin-4 in Primary Astrocytes |
title_sort | high throughput screen identifies chemical modulators of the laminin-induced clustering of dystroglycan and aquaporin-4 in primary astrocytes |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3049781/ https://www.ncbi.nlm.nih.gov/pubmed/21408176 http://dx.doi.org/10.1371/journal.pone.0017559 |
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