Role of protein phosphatases in estrogen-mediated neuroprotection.
The signaling pathways that mediate neurodegeneration are complex and involve a balance between phosphorylation and dephosphorylation of signaling and structural proteins. We have shown previously that 17beta-estradiol and its analogs are potent neuroprotectants. The purpose of this study was to delineate the role of protein phosphatases (PPs) in estrogen neuroprotection against oxidative stress and excitotoxicity. HT-22 cells, C6-glioma cells, and primary rat cortical neurons were exposed to the nonspecific serine/threonine protein phosphatase inhibitors okadaic acid and calyculin A at various concentrations in the presence or absence of 17beta-estradiol and/or glutamate. Okadaic acid and calyculin A caused a dose-dependent decrease in cell viability in HT-22, C6-glioma, and primary rat cortical neurons. 17beta-Estradiol did not show protection against neurotoxic concentrations of either okadaic acid or calyculin A in these cells. In the absence of these serine/threonine protein phosphatase inhibitors, 17beta-estradiol attenuated glutamate toxicity. However, in the presence of effective concentrations of these protein phosphatase inhibitors, 17beta-estradiol protection against glutamate toxicity was lost. Furthermore, glutamate treatment in HT-22 cells and primary rat cortical neurons caused a 50% decrease in levels of PP1, PP2A, and PP2B protein, whereas coadministration of 17beta-estradiol with glutamate prevented the decrease in PP1, PP2A, and PP2B levels. These results suggest that 17beta-estradiol may protect cells against glutamate-induced oxidative stress and excitotoxicity by activating a combination of protein phosphatases.
Yi
Kun Don
KD
Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, Texas 76107, USA.
Chung
Jaegwon
J
Pang
Priscilla
P
Simpkins
James W
JW
D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002477:Cells / Q000187:drug effects; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology; D004967:Estrogens / Q000502:physiology*; D018698:Glutamic Acid / Q000494:pharmacology; D008387:Marine Toxins; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018696:Neuroprotective Agents / Q000378:metabolism*; D019319:Okadaic Acid / Q000494:pharmacology; D010080:Oxazoles / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D013997:Time Factors
D004791:Enzyme Inhibitors; D004967:Estrogens; D008387:Marine Toxins; D018696:Neuroprotective Agents; D010080:Oxazoles; D019319:Okadaic Acid; D018698:Glutamic Acid; D004958:Estradiol; C059041:calyculin A; D019703:Calcineurin; D010749:Phosphoprotein Phosphatases