G-protein-coupled receptor 30/adenylyl cyclase/protein kinase A pathway is involved in estradiol 17ß-D-glucuronide-induced cholestasis

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dc.creator Zucchetti, Andrés E.
dc.creator Barosso, Ismael R.
dc.creator Boaglio, Andrea C.
dc.creator Basiglio, Cecilia Lorena
dc.creator Misczuk, Gisel S.
dc.creator Larocca, M. Cecilia
dc.creator Ruiz, M. Laura
dc.creator Davio, Carlos A.
dc.creator Roma, Marcelo G.
dc.creator Crocenzi, Fernando A.
dc.creator Sánchez Pozzi, Enrique J.
dc.date.accessioned 2018-01-29T23:18:42Z
dc.date.available 2018-01-29T23:18:42Z
dc.date.issued 2014-10
dc.identifier.issn 0270-9139 es
dc.identifier.uri http://hdl.handle.net/2133/10484
dc.description Estradiol-17ß-D-glucuronide (E17G) activates different signaling pathways (e.g., Ca21- dependent protein kinase C, phosphoinositide 3-kinase/protein kinase B, mitogenactivated protein kinases [MAPKs] p38 and extracellular signal-related kinase 1/2, and estrogen receptor alpha) that lead to acute cholestasis in rat liver with retrieval of the canalicular transporters, bile salt export pump (Abcb11) and multidrug resistanceassociated protein 2 (Abcc2). E17G shares with nonconjugated estradiol the capacity to activate these pathways. G-protein-coupled receptor 30 (GPR30) is a receptor implicated in nongenomic effects of estradiol, and the aim of this study was to analyze the potential role of this receptor and its downstream effectors in E17G-induced cholestasis. In vitro, GPR30 inhibition by G15 or its knockdown with small interfering RNA strongly prevented E17G-induced impairment of canalicular transporter function and localization. E17G increased cyclic adenosine monophosphate (cAMP) levels, and this increase was blocked by G15, linking GPR30 to adenylyl cyclase (AC). Moreover, AC inhibition totally prevented E17G insult. E17G also increased protein kinase A (PKA) activity, which was blocked by G15 and AC inhibitors, connecting the links of the pathway, GPR30-AC-PKA. PKA inhibition prevented E17G-induced cholestasis, whereas exchange protein activated directly by cyclic nucleotide/MAPK kinase, another cAMP downstream effector, was not implicated in cAMP cholestatic action. In the perfused rat liver model, inhibition of the GPR30-AC-PKA pathway totally prevented E17G-induced alteration in Abcb11 and Abcc2 function and localization. Conclusion: In conclusion, activation of GPR30-AC-PKA is a key factor in the alteration of canalicular transporter function and localization induced by E17G. Interaction of E17G with GPR30 may be the first event in the cascade of signaling activation. es
dc.description.sponsorship Agencia Nacional de Promoción Científica y Tecnológica (ANPCyT), PICTs 2006 no. 02012 y 2010 no. 1197 es
dc.description.sponsorship Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Proyecto PIP 0691. es
dc.format application/pdf
dc.format.extent 1016 - 1029 es
dc.language.iso eng es
dc.publisher Wiley es
dc.rights openAccess es
dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/2.5/ar/ *
dc.subject AC es
dc.subject Abcb11 es
dc.subject Abcc2 es
dc.subject GPR30 es
dc.subject PKA es
dc.subject cAMP es
dc.title G-protein-coupled receptor 30/adenylyl cyclase/protein kinase A pathway is involved in estradiol 17ß-D-glucuronide-induced cholestasis es
dc.type article
dc.type artículo
dc.type publishedVersion
dc.rights.holder American Association for the Study of Liver Diseases es
dc.rights.holder Universidad Nacional de Rosario es
dc.rights.holder Zucchetti, Andrés E. es
dc.rights.holder Barosso, Ismael R. es
dc.rights.holder Boaglio, Andrea C. es
dc.rights.holder Basiglio, Cecilia Lorena es
dc.rights.holder Misczuk, Gisel S. es
dc.rights.holder Larocca, M. Cecilia es
dc.rights.holder Ruiz, M. Laura es
dc.rights.holder Davio, Carlos A. es
dc.rights.holder Roma, Marcelo G. es
dc.rights.holder Crocenzi, Fernando A. es
dc.rights.holder Sánchez Pozzi, Enrique J. es
dc.rights.holder Wiley es
dc.relation.publisherversion http://onlinelibrary.wiley.com/doi/10.1002/hep.26752/abstract?systemMessage=Please+be+advised+that+we+experienced+an+unexpected+issue+that+occurred+on+Saturday+and+Sunday+January+20th+and+21st+that+caused+the+site+to+be+down+for+an+extended+period+of+time+and+affected+the+ability+of+users+to+access+content+on+Wiley+Online+Library.+This+issue+has+now+been+fully+resolved.++We+apologize+for+any+inconvenience+this+may+have+caused+and+are+working+to+ensure+that+we+can+alert+you+immediately+of+any+unplanned+periods+of+downtime+or+disruption+in+the+future. es
dc.relation.publisherversion http://dx.doi.org/10.1002/hep.26752 es
dc.citation.title Hepatology es
dc.citation.volume 59(3) es
dc.description.fil Fil: Zucchetti, Andrés E. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental (IFISE-CONICET); Argentina. es
dc.description.fil Fil: Barosso, Ismael R. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental (IFISE-CONICET); Argentina. es
dc.description.fil Fil: Boaglio, Andrea C. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental (IFISE-CONICET); Argentina. es
dc.description.fil Fil: Basiglio, Cecilia Lorena. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental (IFISE-CONICET); Argentina. es
dc.description.fil Fil: Misczuk, Gisel S. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental (IFISE-CONICET); Argentina. es
dc.description.fil Fil: Larocca, M. Cecilia. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental (IFISE-CONICET); Argentina es
dc.description.fil Fil: Ruiz, M. Laura. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental (IFISE-CONICET); Argentina. es
dc.description.fil Fil: Davio, Carlos A. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Laboratorio de Farmacología de Receptores; Argentina. es
dc.description.fil Fil: Roma, Marcelo G. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental (IFISE-CONICET); Argentina. es
dc.description.fil Fil: Crocenzi, Fernando A. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental (IFISE-CONICET); Argentina. es
dc.description.fil Fil: Sánchez Pozzi, Enrique J. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental (IFISE-CONICET); Argentina. es
dc.type.collection articulo
dc.type.version publishedVersion es


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