RGD Reference Report - 17beta-estradiol-mediated neuroprotection and ERK activation require a pertussis toxin-sensitive mechanism involving GRK2 and beta-arrestin-1. - Rat Genome Database

RGD Reference Report - 17beta-estradiol-mediated neuroprotection and ERK activation require a pertussis toxin-sensitive mechanism involving GRK2 and beta-arrestin-1. - Rat Genome Database

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17beta-estradiol-mediated neuroprotection and ERK activation require a pertussis toxin-sensitive mechanism involving GRK2 and beta-arrestin-1.
Authors:	Dominguez, R Hu, E Zhou, M Baudry, M
Citation:	Dominguez R, etal., J Neurosci. 2009 Apr 1;29(13):4228-38.
RGD ID:	5509970
Pubmed:	PMID:19339617 (View Abstract at PubMed)
PMCID:	PMC3182118 (View Article at PubMed Central)
DOI:	DOI:10.1523/JNEUROSCI.0550-09.2009 (Journal Full-text)
17-beta-Estradiol (E2) is a steroid hormone involved in numerous bodily functions, including several brain functions. In particular, E2 is neuroprotective against excitotoxicity and other forms of brain injuries, a property that requires the extracellular signal-regulated kinase (ERK) pathway and possibly that of other signaling molecules. The mechanism and identity of the receptor(s) involved remain unclear, although it has been suggested that E2 receptor alpha (ERalpha) and G proteins are involved. We, therefore, investigated whether E2-mediated neuroprotection and ERK activation were linked to pertussis toxin (PTX)-sensitive G-protein-coupled effector systems. Biochemical and image analysis of organotypic hippocampal slices and cortical neuronal cultures showed that E2-mediated neuroprotection as well as E2-induced ERK activation were sensitive to PTX. The sensitivity to PTX suggested a possible role of G-protein- and beta-arrestin-mediated mechanisms. Western immunoblots from E2-treated cortical neuronal cultures revealed an increase in phosphorylation of both G-protein-coupled receptor-kinase 2 and beta-arrestin-1, a G-protein-coupled receptor adaptor protein. Transfection of neurons with beta-arrestin-1 small interfering RNA prevented E2-induced ERK activation. Coimmunoprecipitation experiments indicated that E2 increased the recruitment of beta-arrestin-1 and c-Src to ERalpha. These findings suggested that ERalpha is regulated by a mechanism associated with receptor desensitization and downregulation. In support of this idea, we found that E2 treatment of cortical synaptoneurosomes resulted in internalization of ERalpha, whereas treatment of cortical neurons with the ER agonists E-6-BSA-FITC [beta-estradiol-6-(O-carboxymethyl)oxime-bovine serum albumin conjugated with fluorescein isothiocyanate] and E-6-biotin [1,3,5(10)-estratrien-3,17beta-diol-6-one-6-carboxymethloxime-NH-propyl-bi otin] resulted in agonist internalization. These results demonstrate that E2-mediated neuroprotection and ERK activation involve ERalpha activation of G-protein- and beta-arrestin-mediated mechanisms.

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Object Symbol	Species	Term	Qualifier	Evidence	With	Notes	Source	Original Reference(s)
Arrb1	Rat	nuclear estrogen receptor binding		IPI	Esr1 (Rattus norvegicus)		RGD
Esr1	Rat	protein binding		IPI	Arrb1 (Rattus norvegicus)		RGD

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Genes (Rattus norvegicus)

Arrb1 (arrestin, beta 1)

Esr1 (estrogen receptor 1)

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