Estrogen receptor-independent neuroprotection via protein phosphatase preservation and attenuation of persistent extracellular signal-regulated kinase 1/2 activation.
The mechanism of estrogen-mediated neuroprotection is not yet clear. Estrogens have a variety of modes of action, including transducing signaling events such as activation and/or suppression of the mitogen-activated protein kinase (MAPK) pathway. We have previously shown protein phosphatases to be involved in 17beta-estradiol-mediated neuroprotection. In the present study, we assessed the role of estrogen receptors (ERs) in estrogen-mediated neuroprotection from oxidative/excitotoxic stress and the consequential effects on MAPK signaling. Okadaic acid and calyculin A, nonspecific serine/threonine phosphatase inhibitors, were exposed to cells at various concentrations in the presence or absence of 17alpha-estradiol, the enantiomer of 17beta-estradiol, 2-(1-adamantyl)-3-hydroxyestra-1,3,5(10)-trien-17-one (ZYC3; non-ER-binding estrogen analog), and/or glutamate. All three compounds, which we have shown to have little or no binding to ERalpha and ERbeta, were protective against glutamate toxicity but not against okadaic acid and calyculin A toxicity. In addition, in the presence of effective concentrations of these inhibitors, the protective effects of these estrogen analogs were lost. Glutamate treatment caused a 50% decrease in levels of protein phosphatase 1 (PP1), protein phosphatase 2A (PP2A), and protein phosphatase 2B (calcineurin) (PP2B). Coadministration of ZYC3 with glutamate prevented the decreases in PP1, PP2A, and PP2B levels. Furthermore, glutamate treatment caused a persistent increase in phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 that corresponds with the decrease protein levels of serine/threonine phosphatases. ZYC3 blocked this persistent increase in ERK phosphorylation. These results suggest that estrogens protect cells against glutamate-induced oxidative stress through an ER-independent mediated mechanism that serves to preserve phosphatase activity in the face of oxidative insults, resulting in attenuation of the persistent phosphorylation of ERK associated with neuronal death.
Yi
Kun Don
KD
Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, 3500 Camp Bowie Blvd., Fort Worth, TX 76107, USA.
Cai
Zu Yun
ZY
Covey
Douglas F
DF
Simpkins
James W
JW
D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004967:Estrogens / Q000737:chemistry / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D011960:Receptors, Estrogen / Q000819:agonists / Q000378:metabolism*
D004967:Estrogens; D018696:Neuroprotective Agents; D011960:Receptors, Estrogen; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D010749:Phosphoprotein Phosphatases