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G Protein-Coupled Receptor 30-Dependent Protein Kinase A Pathway Is Critical in Nongenomic Effects of Estrogen in Attenuating Liver Injury after Trauma-Hemorrhage

https://doi.org/10.2353/ajpath.2007.060883Get rights and content

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 trauma-hemorrhage 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.

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Supported by the National Institutes of Health (grants R37 GM-39519 and KO2 AI049960).

Editorial note: A guest editor acted as editor-in-chief for this manuscript. No person at the University of Alabama at Birmingham was involved in the peer review process or final disposition for this article.

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