IFISE 05411
INSTITUTO DE FISIOLOGIA EXPERIMENTAL
Unidad Ejecutora - UE
artículos
Título:
G protein-coupled receptor30-adenylyl cyclase-protein kinase A pathway is involved in estradiol 17ß-d-glucuronide-induced cholestasis.
Autor/es:
ZUCCHETTI A. E.; BAROSSO I.R.; BOAGLIO A. C.; BASIGLIO C.L.; MISZCZUK G. S.; LAROCCA M. C.; RUIZ M. L.; DAVIO C. A.; ROMA M. G.; CROCENZI F. A.; SANCHEZ POZZI E. J.
Revista:
HEPATOLOGY
Editorial:
American Association for the Study of Liver Diseases
Referencias:
Año: 2013 p. 1239 - 1246
ISSN:
0171-6123
Resumen:
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
