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An AKAP-Lbc-RhoA interaction inhibitor promotes the translocation of aquaporin-2 to the plasma membrane of renal collecting duct principal cells

Stimulation of renal collecting duct principal cells with antidiuretic hormone (arginine-vasopressin, AVP) results in inhibition of the small GTPase RhoA and the enrichment of the water channel aquaporin-2 (AQP2) in the plasma membrane. The membrane insertion facilitates water reabsorption from prim...

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Autores principales: Schrade, Katharina, Tröger, Jessica, Eldahshan, Adeeb, Zühlke, Kerstin, Abdul Azeez, Kamal R., Elkins, Jonathan M., Neuenschwander, Martin, Oder, Andreas, Elkewedi, Mohamed, Jaksch, Sarah, Andrae, Karsten, Li, Jinliang, Fernandes, Joao, Müller, Paul Markus, Grunwald, Stephan, Marino, Stephen F., Vukićević, Tanja, Eichhorst, Jenny, Wiesner, Burkhard, Weber, Marcus, Kapiloff, Michael, Rocks, Oliver, Daumke, Oliver, Wieland, Thomas, Knapp, Stefan, von Kries, Jens Peter, Klussmann, Enno
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5786306/
https://www.ncbi.nlm.nih.gov/pubmed/29373579
http://dx.doi.org/10.1371/journal.pone.0191423
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author Schrade, Katharina
Tröger, Jessica
Eldahshan, Adeeb
Zühlke, Kerstin
Abdul Azeez, Kamal R.
Elkins, Jonathan M.
Neuenschwander, Martin
Oder, Andreas
Elkewedi, Mohamed
Jaksch, Sarah
Andrae, Karsten
Li, Jinliang
Fernandes, Joao
Müller, Paul Markus
Grunwald, Stephan
Marino, Stephen F.
Vukićević, Tanja
Eichhorst, Jenny
Wiesner, Burkhard
Weber, Marcus
Kapiloff, Michael
Rocks, Oliver
Daumke, Oliver
Wieland, Thomas
Knapp, Stefan
von Kries, Jens Peter
Klussmann, Enno
author_facet Schrade, Katharina
Tröger, Jessica
Eldahshan, Adeeb
Zühlke, Kerstin
Abdul Azeez, Kamal R.
Elkins, Jonathan M.
Neuenschwander, Martin
Oder, Andreas
Elkewedi, Mohamed
Jaksch, Sarah
Andrae, Karsten
Li, Jinliang
Fernandes, Joao
Müller, Paul Markus
Grunwald, Stephan
Marino, Stephen F.
Vukićević, Tanja
Eichhorst, Jenny
Wiesner, Burkhard
Weber, Marcus
Kapiloff, Michael
Rocks, Oliver
Daumke, Oliver
Wieland, Thomas
Knapp, Stefan
von Kries, Jens Peter
Klussmann, Enno
author_sort Schrade, Katharina
collection PubMed
description Stimulation of renal collecting duct principal cells with antidiuretic hormone (arginine-vasopressin, AVP) results in inhibition of the small GTPase RhoA and the enrichment of the water channel aquaporin-2 (AQP2) in the plasma membrane. The membrane insertion facilitates water reabsorption from primary urine and fine-tuning of body water homeostasis. Rho guanine nucleotide exchange factors (GEFs) interact with RhoA, catalyze the exchange of GDP for GTP and thereby activate the GTPase. However, GEFs involved in the control of AQP2 in renal principal cells are unknown. The A-kinase anchoring protein, AKAP-Lbc, possesses GEF activity, specifically activates RhoA, and is expressed in primary renal inner medullary collecting duct principal (IMCD) cells. Through screening of 18,431 small molecules and synthesis of a focused library around one of the hits, we identified an inhibitor of the interaction of AKAP-Lbc and RhoA. This molecule, Scaff10-8, bound to RhoA, inhibited the AKAP-Lbc-mediated RhoA activation but did not interfere with RhoA activation through other GEFs or activities of other members of the Rho family of small GTPases, Rac1 and Cdc42. Scaff10-8 promoted the redistribution of AQP2 from intracellular vesicles to the periphery of IMCD cells. Thus, our data demonstrate an involvement of AKAP-Lbc-mediated RhoA activation in the control of AQP2 trafficking.
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spelling pubmed-57863062018-02-09 An AKAP-Lbc-RhoA interaction inhibitor promotes the translocation of aquaporin-2 to the plasma membrane of renal collecting duct principal cells Schrade, Katharina Tröger, Jessica Eldahshan, Adeeb Zühlke, Kerstin Abdul Azeez, Kamal R. Elkins, Jonathan M. Neuenschwander, Martin Oder, Andreas Elkewedi, Mohamed Jaksch, Sarah Andrae, Karsten Li, Jinliang Fernandes, Joao Müller, Paul Markus Grunwald, Stephan Marino, Stephen F. Vukićević, Tanja Eichhorst, Jenny Wiesner, Burkhard Weber, Marcus Kapiloff, Michael Rocks, Oliver Daumke, Oliver Wieland, Thomas Knapp, Stefan von Kries, Jens Peter Klussmann, Enno PLoS One Research Article Stimulation of renal collecting duct principal cells with antidiuretic hormone (arginine-vasopressin, AVP) results in inhibition of the small GTPase RhoA and the enrichment of the water channel aquaporin-2 (AQP2) in the plasma membrane. The membrane insertion facilitates water reabsorption from primary urine and fine-tuning of body water homeostasis. Rho guanine nucleotide exchange factors (GEFs) interact with RhoA, catalyze the exchange of GDP for GTP and thereby activate the GTPase. However, GEFs involved in the control of AQP2 in renal principal cells are unknown. The A-kinase anchoring protein, AKAP-Lbc, possesses GEF activity, specifically activates RhoA, and is expressed in primary renal inner medullary collecting duct principal (IMCD) cells. Through screening of 18,431 small molecules and synthesis of a focused library around one of the hits, we identified an inhibitor of the interaction of AKAP-Lbc and RhoA. This molecule, Scaff10-8, bound to RhoA, inhibited the AKAP-Lbc-mediated RhoA activation but did not interfere with RhoA activation through other GEFs or activities of other members of the Rho family of small GTPases, Rac1 and Cdc42. Scaff10-8 promoted the redistribution of AQP2 from intracellular vesicles to the periphery of IMCD cells. Thus, our data demonstrate an involvement of AKAP-Lbc-mediated RhoA activation in the control of AQP2 trafficking. Public Library of Science 2018-01-26 /pmc/articles/PMC5786306/ /pubmed/29373579 http://dx.doi.org/10.1371/journal.pone.0191423 Text en https://creativecommons.org/publicdomain/zero/1.0/ This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 (https://creativecommons.org/publicdomain/zero/1.0/) public domain dedication.
spellingShingle Research Article
Schrade, Katharina
Tröger, Jessica
Eldahshan, Adeeb
Zühlke, Kerstin
Abdul Azeez, Kamal R.
Elkins, Jonathan M.
Neuenschwander, Martin
Oder, Andreas
Elkewedi, Mohamed
Jaksch, Sarah
Andrae, Karsten
Li, Jinliang
Fernandes, Joao
Müller, Paul Markus
Grunwald, Stephan
Marino, Stephen F.
Vukićević, Tanja
Eichhorst, Jenny
Wiesner, Burkhard
Weber, Marcus
Kapiloff, Michael
Rocks, Oliver
Daumke, Oliver
Wieland, Thomas
Knapp, Stefan
von Kries, Jens Peter
Klussmann, Enno
An AKAP-Lbc-RhoA interaction inhibitor promotes the translocation of aquaporin-2 to the plasma membrane of renal collecting duct principal cells
title An AKAP-Lbc-RhoA interaction inhibitor promotes the translocation of aquaporin-2 to the plasma membrane of renal collecting duct principal cells
title_full An AKAP-Lbc-RhoA interaction inhibitor promotes the translocation of aquaporin-2 to the plasma membrane of renal collecting duct principal cells
title_fullStr An AKAP-Lbc-RhoA interaction inhibitor promotes the translocation of aquaporin-2 to the plasma membrane of renal collecting duct principal cells
title_full_unstemmed An AKAP-Lbc-RhoA interaction inhibitor promotes the translocation of aquaporin-2 to the plasma membrane of renal collecting duct principal cells
title_short An AKAP-Lbc-RhoA interaction inhibitor promotes the translocation of aquaporin-2 to the plasma membrane of renal collecting duct principal cells
title_sort akap-lbc-rhoa interaction inhibitor promotes the translocation of aquaporin-2 to the plasma membrane of renal collecting duct principal cells
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5786306/
https://www.ncbi.nlm.nih.gov/pubmed/29373579
http://dx.doi.org/10.1371/journal.pone.0191423
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