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The Journal of Neuroscience, September 13, 2006, 26(37):9439-9447; doi:10.1523/JNEUROSCI.1443-06.2006

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Development/Plasticity/Repair
Estrogen Receptor Protein Interaction with Phosphatidylinositol 3-Kinase Leads to Activation of Phosphorylated Akt and Extracellular Signal-Regulated Kinase 1/2 in the Same Population of Cortical Neurons: A Unified Mechanism of Estrogen Action

Paolo Mannella¹ and Roberta Diaz Brinton^1,2

¹Department of Molecular Pharmacology and Toxicology and ²Program in Neuroscience, University of Southern California, Los Angeles, California 90033

Correspondence should be addressed to Dr. Roberta Diaz Brinton, University of Southern California, Pharmaceutical Sciences Center, 1985 Zonal Avenue, Los Angeles, CA 90033. Email: rbrinton{at}usc.edu

17-Estradiol (E₂)-induced neuroprotection is dependent on mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3K) signaling cascades. We sought to determine whether E₂ neuroprotective mechanisms are mediated by a unified signaling cascade activated by estrogen receptor (ER)–PI3K interaction within the same population of neurons or whether E₂ activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt are independent signaling events in different neuronal populations. Immunoprecipitation of E₂-treated cortical neurons was conducted to determine a protein–protein interaction between ER and the PI3K regulatory subunit p85. Subsequently, cortical neurons were treated with E₂ alone or in presence of MAPK inhibitors or PI3K inhibitors. Results of these analyses indicated a protein–protein interaction between ER and p85 that was time-dependent and consistent with the temporal profile for generation of Akt (pAkt) and ERK1/2 phosphorylation (pERK1/2). E₂-induced phosphorylation of Akt, was first apparent at 10 min and maximal at 30 min. Simultaneously, E₂-induced pERK1/2 was first apparent at 5–10 min and maximal at 30 min. Inhibition of PI3K completely blocked E₂ activation of pAkt at 10 and 30 min and blocked E₂ activation of ERK1/2 at 10 min, which revealed a PI3K-independent activation of ERK at 30 min. Double immunocytochemical labeling for pERK1/2 and pAkt demonstrated that E₂ induced both signaling pathways in the same neurons. These results indicate a unified signaling mechanism for rapid E₂ action that leads to the coordinated activation of both pERK1/2 and pAkt in the same population of neurons. Implications of these results for understanding estrogen mechanism of action in neurons and therapeutic development are considered.

Key words: PI3K; MAPK; estrogen receptor; estrogen therapy; estrogen signaling; therapeutic development; Alzheimer's disease; Akt

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Received Oct. 15, 2005; revised July 10, 2006; accepted July 19, 2006.

Correspondence should be addressed to Dr. Roberta Diaz Brinton, University of Southern California, Pharmaceutical Sciences Center, 1985 Zonal Avenue, Los Angeles, CA 90033. Email: rbrinton{at}usc.edu

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