title: GPR30 mediates estrogen rapid signaling and neuroprotection.
abstract: G-protein-coupled estrogen receptor-30 (GPR30), also known as G-protein estrogen receptor-1 (GPER1), is a putative extranuclear estrogen receptor whose precise functions in the brain are poorly understood. Studies using exogenous administration of the GPR30 agonist, G1 suggests that GPR30 may have a neuroprotective role in cerebral ischemia. However, the physiological role of GPR30 in mediating estrogen (E2)-induced neuroprotection in cerebral ischemia remains unclear. Also unclear is whether GPR30 has a role in mediating rapid signaling by E2 after cerebral ischemia, which is thought to underlie its neuroprotective actions. To address these deficits in our knowledge, the current study examined the effect of antisense oligonucleotide (AS) knockdown of GPR30 in the hippocampal CA1 region upon E2-BSA-induced neuroprotection and rapid kinase signaling in a rat model of global cerebral ischemia (GCI). Immunohistochemistry demonstrated that GPR30 is strongly expressed in the hippocampal CA1 region and dentate gyrus, with less expression in the CA3 region. E2-BSA exerted robust neuroprotection of hippocampal CA1 neurons against GCI, an effect abrogated by AS knockdown of GPR30. Missense control oligonucleotides had no effect upon E2-BSA-induced neuroprotection, indicating specificity of the effect. The GPR30 agonist, G1 also exerted significant neuroprotection against GCI. E2-BSA and G1 also rapidly enhanced activation of the prosurvival kinases, Akt and ERK, while decreasing proapototic JNK activation. Importantly, AS knockdown of GPR30 markedly attenuated these rapid kinase signaling effects of E2-BSA. As a whole, the studies provide evidence of an important role of GPR30 in mediating the rapid signaling and neuroprotective actions of E2 in the hippocampus.
authors.affiliation: Institute of Molecular Medicine and Genetics, Medical College of Georgia, Georgia Regents University, 1120 15th Street, Augusta, GA 30912, USA; Neurobiology Institute, Medical Research Center, Hebei United University, Tangshan 063000, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Tang
authors.affiliation: Institute of Molecular Medicine and Genetics, Medical College of Georgia, Georgia Regents University, 1120 15th Street, Augusta, GA 30912, USA.
authors.forename: Quanguang
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Neurobiology Institute, Medical Research Center, Hebei United University, Tangshan 063000, China.
authors.forename: Licai
authors.initials: L
authors.lastname: Yang
authors.affiliation: Institute of Molecular Medicine and Genetics, Medical College of Georgia, Georgia Regents University, 1120 15th Street, Augusta, GA 30912, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Dong
authors.affiliation: Institute of Molecular Medicine and Genetics, Medical College of Georgia, Georgia Regents University, 1120 15th Street, Augusta, GA 30912, USA.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Khan
authors.affiliation: Neurobiology Institute, Medical Research Center, Hebei United University, Tangshan 063000, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Yang
authors.affiliation: Institute of Molecular Medicine and Genetics, Medical College of Georgia, Georgia Regents University, 1120 15th Street, Augusta, GA 30912, USA. Electronic address: dbrann@gru.edu.
authors.forename: Darrell W
authors.initials: DW
authors.lastname: Brann
authors.affiliation: Institute of Molecular Medicine and Genetics, Medical College of Georgia, Georgia Regents University, 1120 15th Street, Augusta, GA 30912, USA; Neurobiology Institute, Medical Research Center, Hebei United University, Tangshan 063000, China. Electronic address: minruiwang@gmail.com.
authors.forename: Ruimin
authors.initials: R
authors.lastname: Wang
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology*; D056547:CA1 Region, Hippocampal / Q000378:metabolism; D056654:CA3 Region, Hippocampal / Q000378:metabolism; D018891:Dentate Gyrus / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004958:Estradiol / Q000494:pharmacology*; D004967:Estrogens / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000096:biosynthesis; D005260:Female; D055785:Gene Knockdown Techniques; D048031:JNK Mitogen-Activated Protein Kinases / Q000096:biosynthesis; D018696:Neuroprotective Agents / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D012710:Serum Albumin, Bovine / Q000494:pharmacology*; D015398:Signal Transduction
chemical_list: D004967:Estrogens; C520305:Gper1 protein, rat; D018696:Neuroprotective Agents; D043562:Receptors, G-Protein-Coupled; C043090:estradiol-bovine serum albumin; D012710:Serum Albumin, Bovine; D004958:Estradiol; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases
keywords: Estradiol; Estrogen; GPER1; GPR30; Neuroprotection