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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Blotting, Western
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Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors
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Cyclic AMP-Dependent Protein Kinases / metabolism*
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Estradiol / administration & dosage
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Estradiol / pharmacology*
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Estradiol / therapeutic use
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Estrogen Receptor alpha / genetics
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Estrogen Receptor alpha / metabolism
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Estrogens, Conjugated (USP) / administration & dosage
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Estrogens, Conjugated (USP) / pharmacology
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Estrogens, Conjugated (USP) / therapeutic use
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Glutathione Transferase / blood
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Hemorrhage / blood
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Hemorrhage / etiology
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Hemorrhage / prevention & control*
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Hepatocytes / drug effects
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Hepatocytes / metabolism
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Isoenzymes / blood
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Isoquinolines / administration & dosage
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Isoquinolines / pharmacology
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Liver / drug effects*
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Liver / injuries
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Liver / metabolism
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Male
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Models, Biological
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Protein Kinase Inhibitors / pharmacology
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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RNA, Small Interfering / genetics
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Rats
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Rats, Sprague-Dawley
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Receptors, G-Protein-Coupled / genetics
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Receptors, G-Protein-Coupled / metabolism
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Receptors, G-Protein-Coupled / physiology*
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Serum Albumin, Bovine / administration & dosage
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Serum Albumin, Bovine / pharmacology*
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Serum Albumin, Bovine / therapeutic use
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Signal Transduction / drug effects
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Sulfonamides / administration & dosage
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Sulfonamides / pharmacology
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Transfection
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Wounds and Injuries / complications
Substances
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Estrogen Receptor alpha
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Estrogens, Conjugated (USP)
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Isoenzymes
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Isoquinolines
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins c-bcl-2
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RNA, Small Interfering
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Receptors, G-Protein-Coupled
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Sulfonamides
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estradiol-bovine serum albumin
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Serum Albumin, Bovine
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Estradiol
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Glutathione Transferase
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glutathione S-transferase alpha
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Cyclic AMP-Dependent Protein Kinases
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N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide