Linked Life Data

16084662

Source:http://linkedlifedata.com/resource/pubmed/id/16084662

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pubmed-article:16084662pubmed:abstractTextOur group and others have demonstrated that 17beta-estradiol (E2) induces neurotrophic and neuroprotective responses in hippocampal and cortical neurons which are dependent upon the Src/extracellular signal-regulated kinase (ERK) signaling pathways. The purpose of this study was to determine the upstream mechanism(s) that initiates the signaling cascade leading to E2-inducible neuroprotection. We tested the hypothesis that E2 activates rapid Ca(2+) influx in hippocampal neurons, which would lead to activation of the Src/ERK signaling cascade and up-regulation of Bcl-2 protein expression. Using fura-2 ratiometric Ca(2+) imaging, we demonstrated that E2 induced a rapid rise of intracellular Ca(2+) concentration ([Ca(2+)](i)) within minutes of exposure which was blocked by an L-type Ca(2+) channel antagonist. Inhibition of L-type Ca(2+) channels resulted in a loss of E2 activation of the Src/ERK cascade, activation of cyclic-AMP response element binding protein (CREB) and subsequent increase in Bcl-2. Real-time intracellular Ca(2+) imaging combined with pERK immunofluorescence, demonstrated that E2 induced [Ca(2+)](i) was coincident with ERK activation in the same neuron. Small interfering RNA knockdown of CREB resulted in a loss of E2 activation of CREB and subsequent E2-induced increase of Bcl-2 expression. We further demonstrated the presence of specific membrane E2 binding sites in hippocampal neurons. Together, these data indicate that E2-induced Ca(2+) influx via the L-type Ca(2+) channel is required for E2 activation of the Src/ERK/CREB/Bcl-2 signaling. Implications of these data for understanding estrogen action in brain and use of estrogen therapy for prevention of neurodegenerative disease are discussed.lld:pubmed
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pubmed-article:16084662pubmed:authorpubmed-author:ChenSSlld:pubmed
pubmed-article:16084662pubmed:authorpubmed-author:WangJ MJMlld:pubmed
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pubmed-article:16084662pubmed:authorpubmed-author:BrintonR DRDlld:pubmed
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pubmed-article:16084662pubmed:dateRevised2009-11-19lld:pubmed
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pubmed-article:16084662pubmed:articleTitle17Beta-estradiol induced Ca2+ influx via L-type calcium channels activates the Src/ERK/cyclic-AMP response element binding protein signal pathway and BCL-2 expression in rat hippocampal neurons: a potential initiation mechanism for estrogen-induced neuroprotection.lld:pubmed
pubmed-article:16084662pubmed:affiliationNeuroscience Program, University of Southern California, 1985 Zonal Avenue, Los Angeles, CA 90089-9121, USA.lld:pubmed
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pubmed-article:16084662pubmed:publicationTypeResearch Support, U.S. Gov't, P.H.S.lld:pubmed
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