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 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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Author:Katharina Schrade, Jessica Tröger, Adeeb Eldahshan, Kerstin Zühlke, Kamal R. Abdul Azeez, Jonathan M. Elkins, Martin Neuenschwander, Andreas Oder, Mohamed Elkewedi, Sarah Jaksch, Karsten Andrae, Jinliang Li, Joao Fernandes, Paul Markus Müller, Stephan Grunwald, Stephen A. Marino, Tanja Vukićević, Jenny Eichhorst, Burkhard Wiesner, Marcus Weber, Michael Kapiloff, Oliver Rocks, Oliver Daumke, Thomas WielandORCiDGND, Stefan Knapp, Jens Peter von Kries, Enno Klussmann
URN:urn:nbn:de:hebis:30:3-437404
DOI:https://doi.org/10.1371/journal.pone.0191423
ISSN:1932-6203
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/29373579
Parent Title (English):PLoS one
Publisher:PLoS
Place of publication:Lawrence, Kan.
Contributor(s):Rafael Garcia-Mata
Document Type:Article
Language:English
Year of Completion:2018
Date of first Publication:2018/01/26
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2018/02/08
Tag:Cell membranes; Guanine nucleotide exchange factors; Guanosine triphosphatase; Library screening; Luciferase; Phosphorylation; Small molecules; Vesicles
Volume:13
Issue:(1): e0191423
Page Number:30
First Page:1
Last Page:30
Note:
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 public domain dedication.
HeBIS-PPN:426620453
Institutes:Biochemie, Chemie und Pharmazie / Biochemie und Chemie
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 54 Chemie / 540 Chemie und zugeordnete Wissenschaften
Sammlungen:Universitätspublikationen
Licence (German):License LogoGemeinfreies Werk / Public Domain