Protein phosphatase 1, protein phosphatase 2A, and calcineurin play a role in estrogen-mediated neuroprotection.
It is becoming increasingly clear that protein phosphatases are important modulators of cellular function and that disruption of these proteins are involved in neurodegenerative disease processes. Serine/threonine protein phosphatases (PP) such as protein phosphatase PP1, PP2A, and calcineurin are involved in hyperphosphorylation of tau- as well as beta-amyloid-induced cell death. We have previously shown serine/threonine protein phosphatases to be involved in estrogen-mediated neuroprotection. The purpose of this study was to delineate the role of PP1, PP2A, and calcineurin in the mechanism of estrogen mediated neuroprotection against oxidative stress and excitotoxicity. Treatment with protein phosphatases inhibitor II, endothall, or cyclosporin A, which are specific inhibitors of PP1, PP2A, and calcineurin, respectively, did not have an effect on cell viability. However, in combination, these inhibitors adversely affected cell survival, which suggests the importance of serine/threonine protein phosphatases in maintenance of cellular function. Inhibitors of PP1, PP2A, and calcineurin attenuated the protective effects of estrogen against glutamate-induced -neurotoxicity but did not completely abrogate the estrogen-mediated protection. The attenuation of estrogen-induced neuroprotection was achieved through decrease in the activity of theses serine/threonine phosphatases without the concomitant decrease in protein expression. In an animal model, transient middle cerebral artery occlusion caused a 50% decrease in levels of PP1, PP2A, and PP2B ipsilateral to the lesion in a manner that was prevented by estradiol pretreatment. Therefore, we conclude that in the face of cytotoxic challenges in vitro and in vivo, estrogens maintain the function of PP1, PP2A, and calcineurin.
Yi
Kun Don
KD
Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, Texas 76107, USA.
Simpkins
James W
JW
D000818:Animals; D001932:Brain Neoplasms; D019703:Calcineurin / Q000378:metabolism*; D065095:Calcineurin Inhibitors; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D016572:Cyclosporine / Q000494:pharmacology; D003998:Dicarboxylic Acids / Q000494:pharmacology; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology*; D005910:Glioma; D018698:Glutamic Acid / Q000633:toxicity; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000201:enzymology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009498:Neurotoxins / Q000633:toxicity; D019319:Okadaic Acid / Q000633:toxicity; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D054645:Protein Phosphatase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D020521:Stroke / Q000378:metabolism / Q000517:prevention & control
D065095:Calcineurin Inhibitors; D003998:Dicarboxylic Acids; D004791:Enzyme Inhibitors; D004967:Estrogens; D018696:Neuroprotective Agents; D009498:Neurotoxins; C100030:endothall; D019319:Okadaic Acid; D018698:Glutamic Acid; D016572:Cyclosporine; D019703:Calcineurin; D054645:Protein Phosphatase 1; D054648:Protein Phosphatase 2