The Mitogen-Activated Protein Kinase Pathway Mediates Estrogen Neuroprotection after Glutamate Toxicity in Primary Cortical Neurons

Abstract

Pharmacological and biochemical approaches were used to elucidate the involvement of growth factor signaling pathways mediating estrogen neuroprotection in primary cortical neurons after glutamate excitotoxicity. We addressed the activation of mitogen-activated protein kinase (MAPK) signaling pathways, which are activated by growth factors such as nerve growth factor (NGF). Inhibition of MAPK signaling with the MAPK kinase inhibitor PD98059 blocks both NGF and estrogen neuroprotection in these neurons. These results correlate with a rapid and sustained increase in MAPK activity within 30 min of estrogen exposure. The involvement of signaling molecules upstream from MAPK was also examined to determine whether activation of MAPK by estrogen is mediated by tyrosine kinase activity. Estrogen produces a rapid, transient activation of src-family tyrosine kinases and tyrosine phosphorylation of p21(ras)-guanine nucleotide activating protein. Effects of estrogen on neuroprotection, as well as rapid activation of tyrosine kinase and MAPK activity, are blocked by the anti-estrogen ICI 182,780. This provides evidence that activation of the MAPK pathway by estrogen participates in mediating neuroprotection via an estrogen receptor. These results describe a novel mechanism by which cytoplasmic actions of the estrogen receptor may activate the MAPK pathway, thus broadening the understanding of effects of estrogen in neurons.

Inhibition of the SH3 domain-mediated binding of Src to the androgen receptor and its effect on tumor growth

“…The inhibition of stromal cells and growth A new androgen receptor antagonist A Migliaccio et al factor action by the S1 peptide may contribute to the observed strong inhibition of the xenografts growth. The peptide treatment significantly increases the number of cells undergoing apoptosis in LNCaP tumor xenografts in agreement with the view that hormonal activation of Src protects target cells from apoptosis (Singer et al, 1999;Kousteni et al, 2001). In recent years, much evidence has shown that in multiple cell types under different experimental conditions, steroid receptors directly interact with several signaling effectors and trigger various biological effects.…”

Aging and substitutive hormonal therapy influence in regional and subcellular distribution of ERα in female rat brain

“…Therefore, the absolute level of extranuclear ERα is higher when the hormone is administrated. In this sense, non-nuclear estrogen receptor has been widely described as responsible of rapid non-genomic estrogens actions (McCarthy 2008;Vasudevan and Pfaff 2008); raising the possibility that estradiol could play a neuroprotective role through a non-genomic rapid mechanism (Singer et al 1999;Wilson et al 2002). The way of its participation, among many others, could be in the increase of eNOS activity in cerebral blood vessels (McEwen 2001;Milner et al 2001;Toran-Aller et al 2002;Li et al 2003) or the downregulation of GSK3β (Glycogen Synthase Kinase 3β).…”

“…One way involves canonical ER activation, which is constitutively expressed in many brain regions and is able to initiate gene transcription after specifically binding to estradiol (Green and Simpkins 2000;Marin et al 2005). The second way that has been growing interest and refers to the rapid non-genomic (or alternative) signaling pathways, involves extranuclear ER in response to physiological concentration of estrogens to elicit neuroprotection (Singer et al 1999;Adams et al 2002;Mendez et al 2003;Simoncini et al 2003). Recent studies point to a coupling between both mechanisms (for review see Vasudevan and Pfaff 2008).…”

Membrane-initiated estrogen signaling in hypothalamic neurons

“…One view is that both nuclear and plasma membrane-associated ERs might be products of the same genes (Razandi et al, 1999, Boulware et al, 2005, Pedram et al, 2006, Szegõ et al, 2006, Dewing et al, 2007. This belief stems primarily from the fact that many of the rapid effects of E2 can be induced by selective ERα or ERβ ligands, antagonized by the ER antagonist, ICI 182,780, or are lost in animals bearing mutations in ERα and/or ERβ genes (Couse and Korach, 1999, Singer et al, 1999, Dubal et al, 2001, Wade et al, 2001, Abraham et al, 2003, Boulware et al, 2005. Another view is that estrogen activates a unique membrane ER (mER) (Gu et al, 1999, Toran-Allerand, 2004, Toran-Allerand, 2005, Qiu et al, 2006b).…”