Role of protein phosphatases and mitochondria in the neuroprotective effects of estrogens.
In the present treatise, we provide evidence that the neuroprotective and mito-protective effects of estrogens are inexorably linked and involve the ability of estrogens to maintain mitochondrial function during neurotoxic stress. This is achieved by the induction of nuclear and mitochondrial gene expression, the maintenance of protein phosphatases levels in a manner that likely involves modulation of the phosphorylation state of signaling kinases and mitochondrial pro- and anti-apoptotic proteins, and the potent redox/antioxidant activity of estrogens. These estrogen actions are mediated through a combination of estrogens receptor (ER)-mediated effects on nuclear and mitochondrial transcription of protein vital to mitochondrial function, ER-mediated, non-genomic signaling and non-ER-mediated effects of estrogens on signaling and oxidative stress. Collectively, these multifaceted, coordinated action of estrogens leads to their potency in protecting neurons from a wide variety of acute insults as well as chronic neurodegenerative processes.
Department of Pharmacology and Neuroscience, Institute for Aging and Alzheimer's Disease Research, University of North Texas Health Science, Fort Worth, TX 76107, USA. jsimpkin@hsc.unt.edu
James W
JW
Simpkins
Kun Don
KD
Yi
Shao-Hua
SH
Yang
D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004789:Enzyme Activation; D004967:Estrogens / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D008387:Marine Toxins; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D009410:Nerve Degeneration / Q000378:metabolism; D018696:Neuroprotective Agents / Q000378:metabolism*; D010080:Oxazoles / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
D004967:Estrogens; D008387:Marine Toxins; D018696:Neuroprotective Agents; D010080:Oxazoles; C059041:calyculin A; D019703:Calcineurin; D010749:Phosphoprotein Phosphatases