G protein-coupled receptor 30-dependent protein kinase A pathway is critical in nongenomic effects of estrogen in attenuating liver injury after trauma-hemorrhage

Ya Ching Hsieh, Huang Ping Yu, Michael Frink, Takao Suzuki, Mashkoor A. Choudhry, Martin G. Schwacha, Irshad H. Chaudry

Research output: Contribution to journalArticlepeer-review

84 Scopus citations

Abstract

Although nongenomic effects of 17β-estradiol (E2) are mediated via the estrogen receptor α (ER-α), the existence of another novel ER, G protein-coupled receptor 30 (GPR30), has been suggested as a candidate for triggering a broad range of E2-mediated signaling. GPR30 also acts independently of the ER to promote activation of the protein kinase A (PKA) pathway, which protects cells from apoptosis through Bcl-2. In this study, we examined whether the salutary effects of E2 in attenuating hepatic injury after trauma-hemorrhage are mediated via GPR30- or ER-α-regulated activation of PKA-dependent signaling. At 2 hours after trauma-hemorrhage, administration of E2-conjugated to bovine serum albumin (E2-BSA, membrane impermeable) or E2 induced the up-regulation of ER-α and GPR30 and attenuated hepatic injury. This was accompanied by increases in PKA activity and Bcl-2 expression. Inhibition of PKA in E2-BSA-treated traumahemorrhage rats by PKA inhibitor H89 prevented the E2-BSA attenuation of hepatic injury. Isolated hepatocytes were transfected with small interfering RNA to suppress GPR30 or ER. We found that suppression of GPR30 but not ER-α prevented E2-BSA-or E2-induced PKA activation and Bcl-2 expression. These results suggest that the nongenomic salutary effect of E2 in reducing hepatic injury after trauma-hemorrhage is mediated through the PKA-dependent pathway via GPR30 but not ER-α.

Original languageEnglish (US)
Pages (from-to)1210-1218
Number of pages9
JournalAmerican Journal of Pathology
Volume170
Issue number4
DOIs
StatePublished - Apr 2007

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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