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.citation.titleHepatologyes
dc.citation.volume59(3)es
dc.creatorZucchetti, Andrés E.
dc.creatorBarosso, Ismael R.
dc.creatorBoaglio, Andrea C.
dc.creatorBasiglio, Cecilia Lorena
dc.creatorMiszczuk, Gisel Sabrina
dc.creatorLarocca, María Cecilia
dc.creatorRuiz, María Laura
dc.creatorDavio, Carlos A.
dc.creatorRoma, Marcelo Gabriel
dc.creatorCrocenzi, Fernando A.
dc.creatorSánchez Pozzi, Enrique Juan
dc.date.accessioned2018-01-29T23:18:42Z
dc.date.available2018-01-29T23:18:42Z
dc.date.issued2014-10
dc.descriptionEstradiol-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.filFil: Zucchetti, Andrés E. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental (IFISE-CONICET); Argentina.es
dc.description.filFil: Barosso, Ismael R. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental (IFISE-CONICET); Argentina.es
dc.description.filFil: Boaglio, Andrea C. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental (IFISE-CONICET); Argentina.es
dc.description.filFil: Basiglio, Cecilia Lorena. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental (IFISE-CONICET); Argentina.es
dc.description.filFil: Miszczuk, Gisel Sabrina. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental (IFISE-CONICET); Argentina.es
dc.description.filFil: Larocca, María Cecilia. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental (IFISE-CONICET); Argentinaes
dc.description.filFil: Ruiz, M. Laura. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental (IFISE-CONICET); Argentina.es
dc.description.filFil: Davio, Carlos A. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Laboratorio de Farmacología de Receptores; Argentina.es
dc.description.filFil: Roma, Marcelo Gabriel. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental (IFISE-CONICET); Argentina.es
dc.description.filFil: Crocenzi, Fernando A. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental (IFISE-CONICET); Argentina.es
dc.description.filFil: Sánchez Pozzi, Enrique J. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental (IFISE-CONICET); Argentina.es
dc.description.sponsorshipAgencia Nacional de Promoción Científica y Tecnológica (ANPCyT), PICTs 2006 no. 02012 y 2010 no. 1197es
dc.description.sponsorshipConsejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Proyecto PIP 0691.es
dc.formatapplication/pdf
dc.format.extent1016 - 1029es
dc.identifier.issn0270-9139es
dc.identifier.urihttp://hdl.handle.net/2133/10484
dc.language.isoenges
dc.publisherWileyes
dc.relation.publisherversionhttp://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.publisherversionhttp://dx.doi.org/10.1002/hep.26752es
dc.rightsopenAccesses
dc.rights.holderAmerican Association for the Study of Liver Diseaseses
dc.rights.holderUniversidad Nacional de Rosarioes
dc.rights.holderZucchetti, Andrés E.es
dc.rights.holderBarosso, Ismael R.es
dc.rights.holderBoaglio, Andrea C.es
dc.rights.holderBasiglio, Cecilia Lorenaes
dc.rights.holderMiszczuk, Gisel Sabrinaes
dc.rights.holderLarocca, María Ceciliaes
dc.rights.holderRuiz, M. Lauraes
dc.rights.holderDavio, Carlos A.es
dc.rights.holderRoma, Marcelo Gabrieles
dc.rights.holderCrocenzi, Fernando A.es
dc.rights.holderSánchez Pozzi, Enrique J.es
dc.rights.holderWileyes
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/2.5/ar/*
dc.subjectACes
dc.subjectAbcb11es
dc.subjectAbcc2es
dc.subjectGPR30es
dc.subjectPKAes
dc.subjectcAMPes
dc.titleG-protein-coupled receptor 30/adenylyl cyclase/protein kinase A pathway is involved in estradiol 17ß-D-glucuronide-induced cholestasises
dc.typearticle
dc.typeartículo
dc.typepublishedVersion
dc.type.collectionarticulo
dc.type.versionpublishedVersiones

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