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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

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Item Type:Article
Title:An AKAP-Lbc-RhoA interaction inhibitor promotes the translocation of aquaporin-2 to the plasma membrane of renal collecting duct principal cells
Creators Name:Schrade, K. and Tröger, J. and Eldahshan, A. and Zühlke, K. and Abdul Azeez, K.R. and Elkins, J.M. and Neuenschwander, M. and Oder, A. and Elkewedi, M.M.H. and Jaksch, S. and Andrae, K. and Li, J. and Fernandes, J. and Müller, P.M. and Grunwald, S. and Marino, S.F. and Vukićević, T. and Eichhorst, J. and Wiesner, B. and Weber, M. and Kapiloff, M. and Rocks, O. and Daumke, O. and Wieland, T. and Knapp, S. and von Kries, J.P. and Klussmann, E.
Abstract: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.
Keywords:A Kinase Anchor Proteins, Aquaporin 2, Cell Membrane, HEK293 Cells, Kidney Tubules, Collecting, Minor Histocompatibility Antigens, Protein Binding, Protein Transport, Proto-Oncogene Proteins, Small Molecule Libraries, Structure-Activity Relationship, RhoA GTP-Binding Protein
Source:PLoS ONE
ISSN:1932-6203
Publisher:Public Library of Science (U.S.A.)
Volume:13
Number:1
Page Range:e0191423
Date:26 January 2018
Official Publication:https://doi.org/10.1371/journal.pone.0191423
PubMed:View item in PubMed

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