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

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 acu...

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Autores principales: Zucchetti, Andrés E., Barosso, Ismael R., Boaglio, Andrea C., Basiglio, Cecilia Lorena, Miszczuk, Gisel Sabrina, Larocca, María Cecilia, Ruiz, María Laura, Davio, Carlos A., Roma, Marcelo Gabriel, Crocenzi, Fernando A., Sánchez Pozzi, Enrique Juan
Formato: article artículo publishedVersion
Lenguaje:Inglés
Publicado: Wiley 2018
Materias:
AC
Abcb11
Abcc2
GPR30
PKA
cAMP
Acceso en línea:http://hdl.handle.net/2133/10484
http://hdl.handle.net/2133/10484
Aporte de:
Repositorio Hipermedial de la Universidad Nacional de Rosario (UNR) de Universidad Nacional de Rosario
id I15-R121-2133-10484
record_format dspace
institution Universidad Nacional de Rosario
institution_str I-15
repository_str R-121
collection Repositorio Hipermedial de la Universidad Nacional de Rosario (UNR)
language Inglés
topic AC
Abcb11
Abcc2
GPR30
PKA
cAMP
spellingShingle AC
Abcb11
Abcc2
GPR30
PKA
cAMP
Zucchetti, Andrés E.
Barosso, Ismael R.
Boaglio, Andrea C.
Basiglio, Cecilia Lorena
Miszczuk, Gisel Sabrina
Larocca, María Cecilia
Ruiz, María Laura
Davio, Carlos A.
Roma, Marcelo Gabriel
Crocenzi, Fernando A.
Sánchez Pozzi, Enrique Juan
G-protein-coupled receptor 30/adenylyl cyclase/protein kinase A pathway is involved in estradiol 17ß-D-glucuronide-induced cholestasis
topic_facet AC
Abcb11
Abcc2
GPR30
PKA
cAMP
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.
format article
artículo
publishedVersion
author Zucchetti, Andrés E.
Barosso, Ismael R.
Boaglio, Andrea C.
Basiglio, Cecilia Lorena
Miszczuk, Gisel Sabrina
Larocca, María Cecilia
Ruiz, María Laura
Davio, Carlos A.
Roma, Marcelo Gabriel
Crocenzi, Fernando A.
Sánchez Pozzi, Enrique Juan
author_facet Zucchetti, Andrés E.
Barosso, Ismael R.
Boaglio, Andrea C.
Basiglio, Cecilia Lorena
Miszczuk, Gisel Sabrina
Larocca, María Cecilia
Ruiz, María Laura
Davio, Carlos A.
Roma, Marcelo Gabriel
Crocenzi, Fernando A.
Sánchez Pozzi, Enrique Juan
author_sort Zucchetti, Andrés E.
title G-protein-coupled receptor 30/adenylyl cyclase/protein kinase A pathway is involved in estradiol 17ß-D-glucuronide-induced cholestasis
title_short G-protein-coupled receptor 30/adenylyl cyclase/protein kinase A pathway is involved in estradiol 17ß-D-glucuronide-induced cholestasis
title_full G-protein-coupled receptor 30/adenylyl cyclase/protein kinase A pathway is involved in estradiol 17ß-D-glucuronide-induced cholestasis
title_fullStr G-protein-coupled receptor 30/adenylyl cyclase/protein kinase A pathway is involved in estradiol 17ß-D-glucuronide-induced cholestasis
title_full_unstemmed G-protein-coupled receptor 30/adenylyl cyclase/protein kinase A pathway is involved in estradiol 17ß-D-glucuronide-induced cholestasis
title_sort g-protein-coupled receptor 30/adenylyl cyclase/protein kinase a pathway is involved in estradiol 17ß-d-glucuronide-induced cholestasis
publisher Wiley
publishDate 2018
url http://hdl.handle.net/2133/10484
http://hdl.handle.net/2133/10484
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