17β-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

T. W. Wu, J. M. Wang, S. Chen, R. D. Brinton

Research output: Contribution to journalArticlepeer-review

210 Scopus citations

Abstract

Our group and others have demonstrated that 17β-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 Ca2+ imaging, we demonstrated that E2 induced a rapid rise of intracellular Ca2+ concentration ([Ca 2+]i) within minutes of exposure which was blocked by an L-type Ca2+ channel antagonist. Inhibition of L-type Ca2+ 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 Ca2+ imaging combined with pERK immunofluorescence, demonstrated that E2 induced [Ca2+]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 Ca2+ influx via the L-type Ca2+ 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.

Original languageEnglish (US)
Pages (from-to)59-72
Number of pages14
JournalNeuroscience
Volume135
Issue number1
DOIs
StatePublished - 2005
Externally publishedYes

Keywords

  • Calcium-channels
  • Estrogen membrane receptor
  • Gonadal-steroids
  • Neuroprotective mechanisms
  • Signaling-cascades

ASJC Scopus subject areas

  • Neuroscience(all)

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