TY  - JOUR
A1  - Schrade, Katharina
A1  - Tröger, Jessica
A1  - Eldahshan, Adeeb
A1  - Zühlke, Kerstin
A1  - Abdul Azeez, Kamal R.
A1  - Elkins, Jonathan M.
A1  - Neuenschwander, Martin
A1  - Oder, Andreas
A1  - Elkewedi, Mohamed
A1  - Jaksch, Sarah
A1  - Andrae, Karsten
A1  - Li, Jinliang
A1  - Fernandes, Joao
A1  - Müller, Paul Markus
A1  - Grunwald, Stephan
A1  - Marino, Stephen A.
A1  - Vukićević, Tanja
A1  - Eichhorst, Jenny
A1  - Wiesner, Burkhard
A1  - Weber, Marcus
A1  - Kapiloff, Michael
A1  - Rocks, Oliver
A1  - Daumke, Oliver
A1  - Wieland, Thomas
A1  - Knapp, Stefan
A1  - Kries, Jens Peter von
A1  - Klussmann, Enno
T1  - An AKAP-Lbc-RhoA interaction inhibitor promotes the translocation of aquaporin-2 to the plasma membrane of renal collecting duct principal cells
T2  - PLoS one
N2  - 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.
KW  - Cell membranes
KW  - Guanine nucleotide exchange factors
KW  - Small molecules
KW  - Library screening
KW  - Guanosine triphosphatase
KW  - Luciferase
KW  - Phosphorylation
KW  - Vesicles
Y1  - 2018
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/43740
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-437404
SN  - 1932-6203
N1  - 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.
VL  - 13
IS  - (1): e0191423
SP  - 1
EP  - 30
PB  - PLoS
CY  - Lawrence, Kan.
ER  -