G protein-coupled receptor 30-dependent protein kinase A pathway is critical in nongenomic effects of estrogen in attenuating liver injury after trauma-hemorrhage.
Although nongenomic effects of 17beta-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.
Hsieh
Ya-Ching
YC
Center for Surgical Research, University of Alabama at Birmingham, 1670 University Blvd., Volker Hall, Room G094, Birmingham, AL 35294-0019, USA.
Yu
Huang-Ping
HP
Frink
Michael
M
Suzuki
Takao
T
Choudhry
Mashkoor A
MA
Schwacha
Martin G
MG
Chaudry
Irshad H
IH
D000818:Animals; D015153:Blotting, Western; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004958:Estradiol / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D004966:Estrogens, Conjugated (USP) / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D005982:Glutathione Transferase / Q000097:blood; D006470:Hemorrhage / Q000097:blood / Q000209:etiology / Q000517:prevention & control*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D007527:Isoenzymes / Q000097:blood; D007546:Isoquinolines / Q000008:administration & dosage / Q000494:pharmacology; D008099:Liver / Q000187:drug effects* / Q000293:injuries / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012710:Serum Albumin, Bovine / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology; D014162:Transfection; D014947:Wounds and Injuries / Q000150:complications
D047628:Estrogen Receptor alpha; D004966:Estrogens, Conjugated (USP); D007527:Isoenzymes; D007546:Isoquinolines; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D043562:Receptors, G-Protein-Coupled; D013449:Sulfonamides; C043090:estradiol-bovine serum albumin; D012710:Serum Albumin, Bovine; D004958:Estradiol; D005982:Glutathione Transferase; C119995:glutathione S-transferase alpha; D017868:Cyclic AMP-Dependent Protein Kinases; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide