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

Abstract

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.

• Authors: Ya-Ching Hsieh, Huang-Ping Yu, Michael Frink, Takao Suzuki, Mashkoor A Choudhry, Martin G Schwacha, Irshad H Chaudry
• Journal: The American journal of pathology (Am J Pathol) Vol. 170 Issue 4 Pg. 1210-8 (Apr 2007) ISSN: 0002-9440 [Print] United States
• PMID: 17392161 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Estrogen Receptor alpha
• Estrogens, Conjugated (USP)
• Isoenzymes
• Isoquinolines
• Protein Kinase Inhibitors
• Proto-Oncogene Proteins c-bcl-2
• RNA, Small Interfering
• Receptors, G-Protein-Coupled
• Sulfonamides
• estradiol-bovine serum albumin
• Serum Albumin, Bovine
• Estradiol
• Glutathione Transferase
• glutathione S-transferase alpha
• Cyclic AMP-Dependent Protein Kinases
• N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide

Topics

• Animals
• Blotting, Western
• Cyclic AMP-Dependent Protein Kinases (antagonists & inhibitors, metabolism)
• Estradiol (administration & dosage, pharmacology, therapeutic use)
• Estrogen Receptor alpha (genetics, metabolism)
• Estrogens, Conjugated (USP) (administration & dosage, pharmacology, therapeutic use)
• Glutathione Transferase (blood)
• Hemorrhage (blood, etiology, prevention & control)
• Hepatocytes (drug effects, metabolism)
• Isoenzymes (blood)
• Isoquinolines (administration & dosage, pharmacology)
• Liver (drug effects, injuries, metabolism)
• Male
• Models, Biological
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• RNA, Small Interfering (genetics)
• Rats
• Rats, Sprague-Dawley
• Receptors, G-Protein-Coupled (genetics, metabolism, physiology)
• Serum Albumin, Bovine (administration & dosage, pharmacology, therapeutic use)
• Signal Transduction (drug effects)
• Sulfonamides (administration & dosage, pharmacology)
• Transfection
• Wounds and Injuries (complications)