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Submitted on May 10, 2005
Accepted on August 16, 2005
Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0575
* To whom correspondence should be addressed. E-mail: scott.belcher{at}uc.edu.
In neonatal rat cerebellar neurons, 17
-estradiol (E2) rapidly stimulates ERK1/2 phosphorylation through a membrane-associated receptor. Here the mechanism of rapid E2-induced ERK1/2-signaling in primary cultured granule cells was investigated in more detail. The results of these studies show that E2 and ICI182,780, a steroidal antagonist of estrogen receptor transactivation, rapidly increased ERK-signaling with a time course similar to the transient activation induced by epidermal growth factor (EGF). However, EGF receptor (EGFR) autophosphorylation was not increased by E2, and blockade of EGFR tyrosine kinase activity did not abrogate the rapid actions of E2. The involvement of Src-tyrosine kinase activity was demonstrated by detection of increased c-Src phosphorylation in response to E2, and by blockade of E2-induced ERK1/2 activation by inhibition of Src-family tyrosine kinase activity. Inhibition of G
i-signaling or protein kinase A (PKA) activity blocked the ability ICI182,780 to rapidly stimulate ERK-signaling. Under those conditions, E2-treatment induced a rapid and transient suppression of basal ERK1/2 phosphorylation. Protein phosphatase 2A (PP2A) activity was rapidly increased by E2, but not by E2 covalently-linked to BSA. Rapid E2-induced increases in PP2A activity were insensitive to pertussis toxin. The presented evidence indicates that the rapid effects of estrogens on ERK-signaling in cerebellar granule cells are induced through a novel G protein-coupled receptor mechanism that requires PKA and Src-kinase activity to link E2 to the ERK/MAPK signaling module. Along with stimulating ERK-signaling, E2 rapidly activates PP2A via an independent signaling mechanism that may serve as a cell-specific regulator of signal duration.
-estradiol •
estrogen receptor •
ER •
G-protein •
granule cell •
mitogen activate protein kinase •
membrane receptor •
neuron •
non-genomic •
PKA •
PP2A
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