G protein-coupled estrogen receptor is required for the neuritogenic mechanism of 17β-estradiol in developing hippocampal neurons

• Published in: Molecular and cellular endocrinology 2013-06, Vol.372 (1-2), p.105-115
• Main Authors: Ruiz-Palmero, Isabel, Hernando, Maria, Garcia-Segura, Luis M., Arevalo, Maria-Angeles
• Format: Article
• Language: English
• Subjects: Activation; agonists; Akt; Androstadienes - pharmacology; Animals; antagonists; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - metabolism; Blocking; Cells, Cultured; Coupling (molecular); estradiol; Estradiol - analogs & derivatives; Estradiol - pharmacology; Estradiol - physiology; estrogen receptors; Estrogens; Estrogens - pharmacology; Female; G-proteins; G15; Gene Expression; Gene Expression Regulation; GPR30; Hippocampus - cytology; Inhibitors; Mice; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurites - physiology; Neurogenin 3; Neurons; Neurons - metabolism; Neurons - ultrastructure; phosphatidylinositol 3-kinase; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphatidylinositol 3-Kinases - metabolism; Phosphoinositide-3-kinase; Phosphorylation; Primary Cell Culture; Protein Processing, Post-Translational; Proto-Oncogene Proteins c-akt - metabolism; Receptors; Receptors, Estrogen - agonists; Receptors, Estrogen - genetics; Receptors, Estrogen - metabolism; Receptors, G-Protein-Coupled - agonists; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; Signal Transduction; small interfering RNA; transcription factors
• ISSN: 0303-7207; 1872-8057
• DOI: 10.1016/j.mce.2013.03.018

•GPER regulates neurogenin 3 expression and neuritogenesis in hippocampal neurons.•GPER mediates the effect of estradiol on neurogenin 3 expression and neuritogenesis.•GPER regulates PI3K signaling in hippocampal neurons.•PI3K mediates the effect of estradiol on neurogenin 3 expression and neuritogenesis. Estradiol promotes neuritogenesis in developing hippocampal neurons by a mechanism involving the upregulation of neurogenin 3, a Notch-regulated transcription factor. In this study we have explored whether G-protein coupled estrogen receptor 1 (GPER) participates in this hormonal action. GPER agonists (17β-estradiol, G1, ICI 182,780) increased neurogenin 3 expression and neuritogenesis in mouse primary hippocampal neurons and this effect was blocked by the GPER antagonist G15 and by a siRNA for GPER. In addition, GPER agonists increased Akt phosphorylation in ser473, which is indicative of the activation of phosphoinositide-3-kinase (PI3K). G15 or GPER silencing prevented the estrogenic induction of Akt phosphorylation. Furthermore, the PI3K inhibitor wortmannin prevented the effect of G1 and estradiol on neurogenin 3 expression and the effect of estradiol on neuritogenesis. These findings suggest that GPER participates in the control of hippocampal neuritogenesis by a mechanism involving the activation of PI3K signaling.