Estrogen receptor alpha mediates neuronal differentiation and neuroprotection in PC12 cells: critical role of the A/B domain of the receptor

Abstract

Numerous studies, both in vivo and in vitro, have reported neuronal differentiating and neuroprotective actions of estrogens. Most of these estrogenic effects are mediated through specific receptors termed estrogen receptors. The aim of this study was to assess the importance of the N-terminal A/B domain of the estrogen receptor-alpha (ER ) in its neuronal aspects. Consequently, estrogen effects on (i) the transcriptional activity of target genes, (ii) neuronal differentiation and (iii) neuroprotection in PC12 cells transfected with either a full length form of ER or an A/B domain truncated form (ER CF), have been studied. We demonstrate that the maximal estrogen-induced transcriptional activity of reporter genes requires a full length ER , especially when cells are differentiated. Precisely, the transcriptional activity of ER in differentiated cells relies, predominantly, on the activation function AF-1, located in the A/B domain. Furthermore, in PC12 cells stably expressing ER , 17 -estradiol markedly enhances the neurite outgrowth triggered by treatment with nerve growth factor and protects cells from oxidative shocks induced by depletion of glutathione. These estrogenic effects are not observed in non-transfected cells and in cells transfected with the truncated ER, devoid of the A/B domain. Altogether, these results underline the importance of the A/B domain of ER in both the differentiating and the neuroprotective effects of estrogens.

Interaction of estrogen receptor‐α ligand binding domain with nuclear proteins of aging mouse brain

“…ERa is implicated in several brain functions , such as migration of neurons during neuronal differentiation, growth of synapses (Merot et al, 2005), increase in choline acetyltransferase activity (Luine, 1985), and improvement in memory and learning (Korol, 2004). ERa also influences the development and physiology of neurons.…”

Protective effect of estrogen on apoptosis in a cell culture model of Parkinson's disease

“…19 Estrogen is also found to bind to specific membrane receptors to regulate gene transcription, influencing the balance of the cell death suppression gene and cell-death-accelerating gene. [20][21][22] Bcl-x is a member of the Bcl-2 family with apoptosis suppression being its major function. ICE is a proteinase whose main action is to mediate cell death.…”

A new hypothesis of sex-differences in temporomandibular disorders: Estrogen enhances hyperalgesia of inflamed TMJ through modulating voltage-gated sodium channel 1.7 in trigeminal ganglion?

“…Head withdrawal thresholds, food intake and Nav1.7 mRNA and protein expressions in TG will be measured. 6) To examine whether estrogen regulates Nav1.7 expression through ER-ERE interaction in the promoter region of Nav1.7, rat Nav1.7 promoter of 1.5 kb containing the region -1269/-1282 (GGTCAagtTTGCT) and -439/-452 (TGGCAgtaTGACC) will be cloned into luciferase reporter and transfected into nerve growth factor (NGF)-induced and ERa-transfected PC12 cells, which is ERa-null cells and possess neuron property [33]. Luciferase activity will be measured after the cells treated with increasing doses of estrogen for 24 h. 7) To investigate whether estrogen regulates the channel activity of Nav1.7, patch-clamping experiments will be performed.…”