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PLoS One. 2018 Jan 26;13(1):e0191423. doi: 10.1371/journal.pone.0191423. eCollection 2018.

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

Author information

1
Max Delbrück Center for Molecular Medicine Berlin (MDC), Berlin, Germany.
2
Structural Genomics Consortium, University of Oxford, Oxford, United Kingdom.
3
Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin, Germany.
4
Zuse Institute Berlin (ZIB), Germany.
5
University of Miami Miller School of Medicine, Miami, United States of America.
6
Institute of Experimental Pharmacology and Toxicology, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany.
7
DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany.
8
Institute for Pharmaceutical Chemistry and Buchmann Institute, Goethe University, Frankfurt, Germany.
9
DKTK (German Cancer Center Network), partner site Frankfurt/Main, Germany.
10
DZHK (German Centre for Cardiovascular Research), partner site Berlin, Germany.

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.

PMID:
29373579
PMCID:
PMC5786306
DOI:
10.1371/journal.pone.0191423
[Indexed for MEDLINE]
Free PMC Article

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