G protein-coupled receptor30-adenylyl cyclase-protein kinase A pathway is involved in estradiol 17ß-d-glucuronide-induced cholestasis

Autores
Zucchetti, Andrés Ernesto; Barosso, Ismael Ricardo; Boaglio, Andrea Carolina; Basiglio, Cecilia Lorena; Miszczuk, Gisel Sabrina; Larocca, Maria Cecilia; Ruiz, Maria Laura; Davio, Carlos Alberto; Roma, Marcelo Gabriel; Crocenzi, Fernando Ariel; Sanchez Pozzi, Enrique Juan
Año de publicación
2013
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Estradiol-17ß-d-glucuronide (E17G) activates different signaling pathways (such as cPKC, PI3K-Akt, MAP kinases p38 and ERK1/2 and estrogen receptor α) that lead to acute cholestasis in rat liver with retrieval of the canalicular transporters bile salt export pump (Abcb11) and multidrug resistance-associated protein 2 (Abcc2). E17G shares with non-conjugated estradiol the capacity to activate these pathways. The G protein-coupled receptor 30 (GPR30) is a receptor implicated in non-genomic effects of estradiol and the aim of this study was to analyze the potential role of this receptor and its down-stream effectors in E17G-induced cholestasis. In vitro, GPR30 inhibition by G15 or its knock down with siRNA strongly prevented E17G-induced impairment of canalicular transporters function and localization. E17G increased 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 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 Epac/MEK, another cAMP downstream effector, was not implicated in cAMP cholestatic action. In the perfused rat liver model, inhibition of GPR30-AC-PKA pathway totally prevented E17G-induced alteration in Abcb11 and Abcc2 function and localization. In conclusion, activation of GPR30-AC-PKA is a key factor in the alteration of canalicular transporters function and localization induced by E17G. The interaction of E17G with GPR30 may be the first event in the cascade of signaling activation
Fil: Zucchetti, Andrés Ernesto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Fisiología Experimental (i); Argentina
Fil: Barosso, Ismael Ricardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Fisiología Experimental (i); Argentina
Fil: Boaglio, Andrea Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Fisiología Experimental (i); Argentina
Fil: Basiglio, Cecilia Lorena. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Fisiología Experimental (i); Argentina
Fil: Miszczuk, Gisel Sabrina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Fisiología Experimental (i); Argentina
Fil: Larocca, Maria Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Fisiología Experimental (i); Argentina
Fil: Ruiz, Maria Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Fisiología Experimental (i); Argentina
Fil: Davio, Carlos Alberto. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Química Medicinal; Argentina
Fil: Roma, Marcelo Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Fisiología Experimental (i); Argentina
Fil: Crocenzi, Fernando Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Fisiología Experimental (i); Argentina
Fil: Sanchez Pozzi, Enrique Juan. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Fisiología Experimental (i); Argentina
Materia
Ac
Abcb11
Abcc2
Gpr30
Pka
Camp
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/6119
Acceder
id CONICETDig_9f7c87093a1c444652ac3bbe19f6fdfb
oai_identifier_str oai:ri.conicet.gov.ar:11336/6119
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling G protein-coupled receptor30-adenylyl cyclase-protein kinase A pathway is involved in estradiol 17ß-d-glucuronide-induced cholestasisZucchetti, Andrés ErnestoBarosso, Ismael RicardoBoaglio, Andrea CarolinaBasiglio, Cecilia LorenaMiszczuk, Gisel SabrinaLarocca, Maria CeciliaRuiz, Maria LauraDavio, Carlos AlbertoRoma, Marcelo GabrielCrocenzi, Fernando ArielSanchez Pozzi, Enrique JuanAcAbcb11Abcc2Gpr30PkaCamphttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Estradiol-17ß-d-glucuronide (E17G) activates different signaling pathways (such as cPKC, PI3K-Akt, MAP kinases p38 and ERK1/2 and estrogen receptor α) that lead to acute cholestasis in rat liver with retrieval of the canalicular transporters bile salt export pump (Abcb11) and multidrug resistance-associated protein 2 (Abcc2). E17G shares with non-conjugated estradiol the capacity to activate these pathways. The G protein-coupled receptor 30 (GPR30) is a receptor implicated in non-genomic effects of estradiol and the aim of this study was to analyze the potential role of this receptor and its down-stream effectors in E17G-induced cholestasis. In vitro, GPR30 inhibition by G15 or its knock down with siRNA strongly prevented E17G-induced impairment of canalicular transporters function and localization. E17G increased 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 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 Epac/MEK, another cAMP downstream effector, was not implicated in cAMP cholestatic action. In the perfused rat liver model, inhibition of GPR30-AC-PKA pathway totally prevented E17G-induced alteration in Abcb11 and Abcc2 function and localization. In conclusion, activation of GPR30-AC-PKA is a key factor in the alteration of canalicular transporters function and localization induced by E17G. The interaction of E17G with GPR30 may be the first event in the cascade of signaling activationFil: Zucchetti, Andrés Ernesto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Fisiología Experimental (i); ArgentinaFil: Barosso, Ismael Ricardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Fisiología Experimental (i); ArgentinaFil: Boaglio, Andrea Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Fisiología Experimental (i); ArgentinaFil: Basiglio, Cecilia Lorena. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Fisiología Experimental (i); ArgentinaFil: Miszczuk, Gisel Sabrina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Fisiología Experimental (i); ArgentinaFil: Larocca, Maria Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Fisiología Experimental (i); ArgentinaFil: Ruiz, Maria Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Fisiología Experimental (i); ArgentinaFil: Davio, Carlos Alberto. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Química Medicinal; ArgentinaFil: Roma, Marcelo Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Fisiología Experimental (i); ArgentinaFil: Crocenzi, Fernando Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Fisiología Experimental (i); ArgentinaFil: Sanchez Pozzi, Enrique Juan. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Fisiología Experimental (i); ArgentinaWiley2013-10info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/6119Zucchetti, Andrés Ernesto; Barosso, Ismael Ricardo; Boaglio, Andrea Carolina; Basiglio, Cecilia Lorena; Miszczuk, Gisel Sabrina; et al.; G protein-coupled receptor30-adenylyl cyclase-protein kinase A pathway is involved in estradiol 17ß-d-glucuronide-induced cholestasis; Wiley; Hepatology (baltimore, Md.); 59; 3; 10-2013; 1016-10290270-9139enginfo:eu-repo/semantics/altIdentifier/url/http://onlinelibrary.wiley.com/wol1/doi/10.1002/hep.26752/abstractinfo:eu-repo/semantics/altIdentifier/doi/10.1002/hep.26752info:eu-repo/semantics/altIdentifier/doi/info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-22T11:29:57Zoai:ri.conicet.gov.ar:11336/6119instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-10-22 11:29:58.143CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv G protein-coupled receptor30-adenylyl cyclase-protein kinase A pathway is involved in estradiol 17ß-d-glucuronide-induced cholestasis
title G protein-coupled receptor30-adenylyl cyclase-protein kinase A pathway is involved in estradiol 17ß-d-glucuronide-induced cholestasis
spellingShingle G protein-coupled receptor30-adenylyl cyclase-protein kinase A pathway is involved in estradiol 17ß-d-glucuronide-induced cholestasis
Zucchetti, Andrés Ernesto
Ac
Abcb11
Abcc2
Gpr30
Pka
Camp
title_short G protein-coupled receptor30-adenylyl cyclase-protein kinase A pathway is involved in estradiol 17ß-d-glucuronide-induced cholestasis
title_full G protein-coupled receptor30-adenylyl cyclase-protein kinase A pathway is involved in estradiol 17ß-d-glucuronide-induced cholestasis
title_fullStr G protein-coupled receptor30-adenylyl cyclase-protein kinase A pathway is involved in estradiol 17ß-d-glucuronide-induced cholestasis
title_full_unstemmed G protein-coupled receptor30-adenylyl cyclase-protein kinase A pathway is involved in estradiol 17ß-d-glucuronide-induced cholestasis
title_sort G protein-coupled receptor30-adenylyl cyclase-protein kinase A pathway is involved in estradiol 17ß-d-glucuronide-induced cholestasis
dc.creator.none.fl_str_mv Zucchetti, Andrés Ernesto
Barosso, Ismael Ricardo
Boaglio, Andrea Carolina
Basiglio, Cecilia Lorena
Miszczuk, Gisel Sabrina
Larocca, Maria Cecilia
Ruiz, Maria Laura
Davio, Carlos Alberto
Roma, Marcelo Gabriel
Crocenzi, Fernando Ariel
Sanchez Pozzi, Enrique Juan
author Zucchetti, Andrés Ernesto
author_facet Zucchetti, Andrés Ernesto
Barosso, Ismael Ricardo
Boaglio, Andrea Carolina
Basiglio, Cecilia Lorena
Miszczuk, Gisel Sabrina
Larocca, Maria Cecilia
Ruiz, Maria Laura
Davio, Carlos Alberto
Roma, Marcelo Gabriel
Crocenzi, Fernando Ariel
Sanchez Pozzi, Enrique Juan
author_role author
author2 Barosso, Ismael Ricardo
Boaglio, Andrea Carolina
Basiglio, Cecilia Lorena
Miszczuk, Gisel Sabrina
Larocca, Maria Cecilia
Ruiz, Maria Laura
Davio, Carlos Alberto
Roma, Marcelo Gabriel
Crocenzi, Fernando Ariel
Sanchez Pozzi, Enrique Juan
author2_role author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Ac
Abcb11
Abcc2
Gpr30
Pka
Camp
topic Ac
Abcb11
Abcc2
Gpr30
Pka
Camp
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Estradiol-17ß-d-glucuronide (E17G) activates different signaling pathways (such as cPKC, PI3K-Akt, MAP kinases p38 and ERK1/2 and estrogen receptor α) that lead to acute cholestasis in rat liver with retrieval of the canalicular transporters bile salt export pump (Abcb11) and multidrug resistance-associated protein 2 (Abcc2). E17G shares with non-conjugated estradiol the capacity to activate these pathways. The G protein-coupled receptor 30 (GPR30) is a receptor implicated in non-genomic effects of estradiol and the aim of this study was to analyze the potential role of this receptor and its down-stream effectors in E17G-induced cholestasis. In vitro, GPR30 inhibition by G15 or its knock down with siRNA strongly prevented E17G-induced impairment of canalicular transporters function and localization. E17G increased 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 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 Epac/MEK, another cAMP downstream effector, was not implicated in cAMP cholestatic action. In the perfused rat liver model, inhibition of GPR30-AC-PKA pathway totally prevented E17G-induced alteration in Abcb11 and Abcc2 function and localization. In conclusion, activation of GPR30-AC-PKA is a key factor in the alteration of canalicular transporters function and localization induced by E17G. The interaction of E17G with GPR30 may be the first event in the cascade of signaling activation
Fil: Zucchetti, Andrés Ernesto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Fisiología Experimental (i); Argentina
Fil: Barosso, Ismael Ricardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Fisiología Experimental (i); Argentina
Fil: Boaglio, Andrea Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Fisiología Experimental (i); Argentina
Fil: Basiglio, Cecilia Lorena. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Fisiología Experimental (i); Argentina
Fil: Miszczuk, Gisel Sabrina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Fisiología Experimental (i); Argentina
Fil: Larocca, Maria Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Fisiología Experimental (i); Argentina
Fil: Ruiz, Maria Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Fisiología Experimental (i); Argentina
Fil: Davio, Carlos Alberto. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Química Medicinal; Argentina
Fil: Roma, Marcelo Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Fisiología Experimental (i); Argentina
Fil: Crocenzi, Fernando Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Fisiología Experimental (i); Argentina
Fil: Sanchez Pozzi, Enrique Juan. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Fisiología Experimental (i); Argentina
description Estradiol-17ß-d-glucuronide (E17G) activates different signaling pathways (such as cPKC, PI3K-Akt, MAP kinases p38 and ERK1/2 and estrogen receptor α) that lead to acute cholestasis in rat liver with retrieval of the canalicular transporters bile salt export pump (Abcb11) and multidrug resistance-associated protein 2 (Abcc2). E17G shares with non-conjugated estradiol the capacity to activate these pathways. The G protein-coupled receptor 30 (GPR30) is a receptor implicated in non-genomic effects of estradiol and the aim of this study was to analyze the potential role of this receptor and its down-stream effectors in E17G-induced cholestasis. In vitro, GPR30 inhibition by G15 or its knock down with siRNA strongly prevented E17G-induced impairment of canalicular transporters function and localization. E17G increased 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 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 Epac/MEK, another cAMP downstream effector, was not implicated in cAMP cholestatic action. In the perfused rat liver model, inhibition of GPR30-AC-PKA pathway totally prevented E17G-induced alteration in Abcb11 and Abcc2 function and localization. In conclusion, activation of GPR30-AC-PKA is a key factor in the alteration of canalicular transporters function and localization induced by E17G. The interaction of E17G with GPR30 may be the first event in the cascade of signaling activation
publishDate 2013
dc.date.none.fl_str_mv 2013-10
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/6119
Zucchetti, Andrés Ernesto; Barosso, Ismael Ricardo; Boaglio, Andrea Carolina; Basiglio, Cecilia Lorena; Miszczuk, Gisel Sabrina; et al.; G protein-coupled receptor30-adenylyl cyclase-protein kinase A pathway is involved in estradiol 17ß-d-glucuronide-induced cholestasis; Wiley; Hepatology (baltimore, Md.); 59; 3; 10-2013; 1016-1029
0270-9139
url http://hdl.handle.net/11336/6119
identifier_str_mv Zucchetti, Andrés Ernesto; Barosso, Ismael Ricardo; Boaglio, Andrea Carolina; Basiglio, Cecilia Lorena; Miszczuk, Gisel Sabrina; et al.; G protein-coupled receptor30-adenylyl cyclase-protein kinase A pathway is involved in estradiol 17ß-d-glucuronide-induced cholestasis; Wiley; Hepatology (baltimore, Md.); 59; 3; 10-2013; 1016-1029
0270-9139
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://onlinelibrary.wiley.com/wol1/doi/10.1002/hep.26752/abstract
info:eu-repo/semantics/altIdentifier/doi/10.1002/hep.26752
info:eu-repo/semantics/altIdentifier/doi/
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
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dc.publisher.none.fl_str_mv Wiley
publisher.none.fl_str_mv Wiley
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 12.982451

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