title: Extracellular ATP counteracts the ERK1/2-mediated death-promoting signaling cascades in astrocytes.
abstract: Oxidative stress is the main cause of neuronal death in pathological conditions. Hydrogen peroxide (H(2)O(2)), one of the reactive oxygen species, activates many intracellular signaling cascades including src family and mitogen-activated protein kinases (MAPKs), some of which are critically involved in the induction of cellular damage. We previously showed that H(2)O(2)-induced cell death in astrocytes and adenosine 5(')-triphosphate (ATP), acting on P2Y(1) receptors, had a protective effect. Here, we examined the H(2)O(2)-induced changes in intracellular signaling cascades that promote cell death in astrocytes, showing the molecular mechanisms by which the activation of P2Y(1) receptors counteracts such signals. Although H(2)O(2) activated three MAPKs including ERK1/2, p38, and JNK, only the activation of ERK1/2 participated in the H(2)O(2)-evoked cell death. H(2)O(2) induced a sustained activation of ERK1/2 mainly in the nucleus region, which was well in accordance with the H(2)O(2)-induced cell death. H(2)O(2) also activated the src tyrosine kinase family, which was an upstream signal for ERK1/2. Activation of P2Y(1) receptors by 2methylthio-ADP (2MeSADP) inhibited the H(2)O(2)-evoked activation of src tyrosine kinase, resulting in the inhibition of the phosphorylated-ERK1/2 accumulation in the nucleus. 2MeSADP enhanced the gene expression and activity of protein tyrosine phosphatase (PTP), which was responsible for the inhibition of src tyrosine kinase. Thioredoxin reductase, another cytoprotective gene we previously showed to be upregulated by 2MeSADP, also controlled the activity of PTP. Taken together, ATP, acting on P2Y(1) receptors, upregulates the PTP expression and its activity, which counteracts the H(2)O(2)-promoted death signaling cascades including ERK1/2 and its upstream signal src tyrosine kinase in astrocytes.
authors.affiliation: Division of Pharmacology, National Institute of Health Sciences, Setagaya, Tokyo 158-8501, Japan.
authors.forename: Youichi
authors.initials: Y
authors.lastname: Shinozaki
authors.forename: Schuichi
authors.initials: S
authors.lastname: Koizumi
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Ohno
authors.forename: Taku
authors.initials: T
authors.lastname: Nagao
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Inoue
mesh_terms: D000244:Adenosine Diphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects* / Q000201:enzymology; D001921:Brain / Q000201:enzymology / Q000503:physiopathology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002467:Cell Nucleus / Q000187:drug effects / Q000201:enzymology; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D045604:Extracellular Fluid / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000494:pharmacology; D048052:Mitogen-Activated Protein Kinase 3 / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D017027:Protein Tyrosine Phosphatases / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D018048:Receptors, Purinergic P2 / Q000187:drug effects / Q000378:metabolism*; D058472:Receptors, Purinergic P2Y1; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013873:Thionucleotides / Q000494:pharmacology; D013880:Thioredoxin-Disulfide Reductase / Q000378:metabolism; D019061:src-Family Kinases / Q000187:drug effects / Q000378:metabolism
chemical_list: D018048:Receptors, Purinergic P2; D058472:Receptors, Purinergic P2Y1; D013873:Thionucleotides; C002480:methylthio-ADP; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D006861:Hydrogen Peroxide; D013880:Thioredoxin-Disulfide Reductase; D019061:src-Family Kinases; D048052:Mitogen-Activated Protein Kinase 3; D017027:Protein Tyrosine Phosphatases