17‐β‐Estradiol‐mediated activation of extracellular‐signal regulated kinase, phosphatidylinositol 3‐kinase/protein kinase B‐Akt and N‐methyl‐d‐aspartate receptor phosphorylation in cortical synaptoneurosomes

Abstract

In addition to its well-known activational mechanism, the steroid hormone 17-b-estradiol (E2) has been shown to rapidly activate various signal transduction pathways that could participate in estrogen-mediated regulation of synaptic plasticity. Although the mechanisms underlying these effects are not clearly understood, it has been repeatedly suggested that they involve a plasma membrane receptor which has direct links to several intracellular signaling cascades. To further address the question of whether E2 acts directly at the synapse and through membrane-bound receptors, we studied the effects of E2 and of ligands of estrogen receptors on various signaling pathways in cortical synaptoneurosomes. Our results demonstrate that E2 elicits N-methyl-D-aspartate receptor phosphorylation and activates the extracellular signal-regulated kinase and the phosphatidylinositol 3-kinase/Akt signal transduction pathways in this cortical membrane preparation. Furthermore, we provide evidence for the presence of a membrane-bound estrogen receptor responsible for these effects in cortical synaptoneurosomes. Our study demonstrates that E2 directly acts at cortical synapses, and that synaptoneurosomes provide a useful system to investigate the mechanisms by which E2 regulates synaptic transmission and plasticity.

Estradiol Targets Synaptic Proteins to Induce Glutamatergic Synapse Formation in Cultured Hippocampal Neurons: Critical Role of Estrogen Receptor-

“…Recent evidence confirms that estradiol can act at the level of the synapse to activate various intracellular signaling pathways through membrane ERs. These events appear to depend on ER-␣ and ER-␤ because both agonists induced ERK activation and associated NMDAR phosphorylation (Dominguez et al, 2007).…”

“…In addition, estrogen-induced synaptogenesis clearly depends on postsynaptic NMDA receptor (NMDAR) transmission because antagonists of NMDARs block estradiol-induced synaptogenesis in vivo (Weiland, 1992;Woolley and McEwen, 1994) and in vitro (Murphy and Segal, 1996). Recent studies report that membrane-bound ER activation regulates NMDAR phosphorylation in cortical synaptoneurosomes, demonstrating direct action of estradiol at synapses (Dominguez et al, 2007). Because NMDARs play a critical role in establishing appropriate synaptic connections in the developing brain (Cline et al, 1987), analyzing the impact of estradiol on NMDAR localization may begin to reveal how estradiol drives synaptogenesis and affects development.…”

G-Protein-Coupled Receptor 30 Mediates Rapid Neuroprotective Effects of Estrogen via Depression of NR2B-Containing NMDA Receptors

“…Once activated, these receptors translocate to the nucleus where they function as ligand-dependent transcription factors (Hall et al, 2001). In contrast, fast nongenomic effects are mediated by classic receptors (ER␣ and ER␤) and specific G-protein-coupled receptors and ER-X] (Revankar et al, 2005;Abe et al, 2008) that regulate ligand-gated ion channels and neurotransmitter transporters (Carrer et al, 2003;Dominguez et al, 2007;Chu et al, 2009;Grassi et al, 2009).…”

“…This receptor is widely distributed and has numerous physiologic or pathologic functions in the CNS (Dominguez et al, 2007;Chu et al, 2009;Grassi et al, 2009). Through genomic and nongenomic mechanisms, E2 modulates neuronal excitability and rapidly increases signal transmission by regulating both NMDA and non-NMDA glutamate receptors (NMDARs) (Wong and Moss, 1992;Foy et al, 1999).…”

Long-Term Potentiation in the Rat Medial Vestibular Nuclei Depends on Locally Synthesized 17β-Estradiol

“…The fast nongenomic effects are mediated by specific membrane receptors (ER␣ and ER␤) and G-proteincoupled receptors (GPR-30 and ER-X) (Toran-Allerand et al, 2002;Qiu et al, 2003;Pedram et al, 2006;Morisette et al, 2008;Raz et al, 2008) that regulate ligand-gated ion channels and neurotransmitter transporters (Wong et al, 1996;Kelly et al, 2002;Levin, 2002;Carrer et al, 2003;Dominguez et al, 2007). Through these mechanisms, E 2 rapidly increases signal transmission by facilitating non-NMDA and NMDA receptors (NMDARs) (Wong and Moss, 1992;Gu and Moss, 1996;Foy et al, 1999), and inhibiting GABA release (Murphy et al, 1998;Rudick and Wooley, 2001).…”