17beta-estradiol-mediated neuroprotection and ERK activation require a pertussis toxin-sensitive mechanism involving GRK2 and beta-arrestin-1.

[gm1 gangliosidosis]

17 -beta -Estradiol (E 2 ) is a steroid hormone involved in numerous bodily functions , including several brain functions . In particular , E 2 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 E 2 receptor alpha (ERalpha ) and G proteins are involved . We , therefore , investigated whether E 2 -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 E 2 -mediated neuroprotection as well as E 2 -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 E 2 -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 E 2 -induced ERK activation . Coimmunoprecipitation experiments indicated that E 2 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 E 2 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 ,17 beta -diol-6 -one -6 -carboxymethloxime-NH -propyl-biotin ] resulted in agonist internalization . These results demonstrate that E 2 -mediated neuroprotection and ERK activation involve ERalpha activation of G-protein- and beta -arrestin-mediated mechanisms .

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gm1 gangliosidosis

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