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(American Journal of Pathology. 2007;170:1210-1218.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.060883

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 and Irshad H. Chaudry

From the Center for Surgical Research and Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama

Although nongenomic effects of 17ß-estradiol (E2) are mediated via the estrogen receptor {alpha} (ER-{alpha}), 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-{alpha}-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-{alpha} 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-{alpha} 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-{alpha}.




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