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...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
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Public Library of Science
2018
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| _version_ | 1797076148398587904 |
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| author | Schrade, K Tröger, J Eldahshan, A Zühlke, K Abdul Azeez, K Elkins, J Neuenschwander, M Oder, A Elkewedi, M Jaksch, S Andrae, K Li, J Fernandes, J Müller, P Grunwald, S Marino, S Vukićević, T Eichhorst, J Wiesner, B Weber, M Kapiloff, M Rocks, O Daumke, O Wieland, T Knapp, S von Kries, J Klussmann, E |
| author_facet | Schrade, K Tröger, J Eldahshan, A Zühlke, K Abdul Azeez, K Elkins, J Neuenschwander, M Oder, A Elkewedi, M Jaksch, S Andrae, K Li, J Fernandes, J Müller, P Grunwald, S Marino, S Vukićević, T Eichhorst, J Wiesner, B Weber, M Kapiloff, M Rocks, O Daumke, O Wieland, T Knapp, S von Kries, J Klussmann, E |
| author_sort | Schrade, K |
| collection | OXFORD |
| 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. |
| first_indexed | 2024-03-07T00:00:04Z |
| format | Journal article |
| id | oxford-uuid:75a06b2b-8033-4895-8057-abc3d60aa207 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T00:00:04Z |
| publishDate | 2018 |
| publisher | Public Library of Science |
| record_format | dspace |
| spelling | oxford-uuid:75a06b2b-8033-4895-8057-abc3d60aa2072022-03-26T20:10:39ZAn AKAP-Lbc-RhoA interaction inhibitor promotes the translocation of aquaporin-2 to the plasma membrane of renal collecting duct principal cells.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:75a06b2b-8033-4895-8057-abc3d60aa207EnglishSymplectic Elements at OxfordPublic Library of Science2018Schrade, KTröger, JEldahshan, AZühlke, KAbdul Azeez, KElkins, JNeuenschwander, MOder, AElkewedi, MJaksch, SAndrae, KLi, JFernandes, JMüller, PGrunwald, SMarino, SVukićević, TEichhorst, JWiesner, BWeber, MKapiloff, MRocks, ODaumke, OWieland, TKnapp, Svon Kries, JKlussmann, EStimulation 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. |
| spellingShingle | Schrade, K Tröger, J Eldahshan, A Zühlke, K Abdul Azeez, K Elkins, J Neuenschwander, M Oder, A Elkewedi, M Jaksch, S Andrae, K Li, J Fernandes, J Müller, P Grunwald, S Marino, S Vukićević, T Eichhorst, J Wiesner, B Weber, M Kapiloff, M Rocks, O Daumke, O Wieland, T Knapp, S von Kries, J Klussmann, E 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 |
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