Neuroprotection elicited by P2Y13 receptors against genotoxic stress by inducing DUSP2 expression and MAPK signaling recovery.
Nucleotides activating P2Y13 receptors display neuroprotective actions against different apoptotic stimuli in cerebellar granule neurons. In the present study, P2Y13 neuroprotection was analyzed in conditions of genotoxic stress. Exposure to cisplatin and UV radiation induced caspase-3-dependent apoptotic cell death, and p38 MAPK signaling de-regulation. Pre-treatment with P2Y13 nucleotide agonist, 2methyl-thio-ADP (2MeSADP), restored granule neuron survival and prevented p38 long-lasting activation induced by cytotoxic treatments. Microarray gene expression analysis in 2MeSADP-stimulated cells revealed over-representation of genes related to protein phosphatase activity. Among them, dual-specificity phosphatase-2, DUSP2, was validated as a transcriptional target for P2Y13 receptors by QPCR. This effect could explain 2MeSADP ability to dephosphorylate a DUSP2 substrate, p38, reestablishing the inactive form. In addition, cisplatin-induced p38 sustained activation correlated perfectly with progressive reduction in DUSP2 expression. In conclusion, P2Y13 receptors regulate DUSP2 expression and contribute to p38 signaling homeostasis and survival in granule neurons.
Biochemistry Department, Veterinary Faculty, Complutense University of Madrid, Institute of Neurochemistry (IUIN), Madrid, Spain; Health Research Institute of the Hospital Clinico San Carlos (IdISSC), Spain.
Verónica
V
Morente
Biochemistry Department, Veterinary Faculty, Complutense University of Madrid, Institute of Neurochemistry (IUIN), Madrid, Spain; Health Research Institute of the Hospital Clinico San Carlos (IdISSC), Spain. Electronic address: rpsen@vet.ucm.es.
Raquel
R
Pérez-Sen
Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg-Universität Mainz, Germany.
Felipe
F
Ortega
Bioinformatics and Genomics Programme, Centre for Genomic Regulation (CRG), Dr. Aiguader, 88., Universitat Pompeu Fabra (UPF), 08003 Barcelona, Spain.
Jaime
J
Huerta-Cepas
Biochemistry Department, Veterinary Faculty, Complutense University of Madrid, Institute of Neurochemistry (IUIN), Madrid, Spain; Health Research Institute of the Hospital Clinico San Carlos (IdISSC), Spain.
Esmerilda G
EG
Delicado
Biochemistry Department, Veterinary Faculty, Complutense University of Madrid, Institute of Neurochemistry (IUIN), Madrid, Spain; Health Research Institute of the Hospital Clinico San Carlos (IdISSC), Spain.
M Teresa
MT
Miras-Portugal
D000244:Adenosine Diphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000528:radiation effects; D002467:Cell Nucleus / Q000187:drug effects / Q000201:enzymology / Q000528:radiation effects; D002531:Cerebellum / Q000473:pathology; D002945:Cisplatin / Q000494:pharmacology; D019610:Cytoprotection / Q000187:drug effects / Q000528:radiation effects; D004249:DNA Damage; D054641:Dual Specificity Phosphatase 2 / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects / Q000528:radiation effects; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000528:radiation effects; D008954:Models, Biological; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D018696:Neuroprotective Agents / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects / Q000528:radiation effects; D051381:Rats; D017208:Rats, Wistar; D018048:Receptors, Purinergic P2 / Q000378:metabolism*; D013873:Thionucleotides / Q000494:pharmacology; D014466:Ultraviolet Rays; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D018696:Neuroprotective Agents; C486690:P2ry13 protein, rat; D018048:Receptors, Purinergic P2; D013873:Thionucleotides; C002480:methylthio-ADP; D000244:Adenosine Diphosphate; D048051:p38 Mitogen-Activated Protein Kinases; D054641:Dual Specificity Phosphatase 2; C517034:Dusp2 protein, rat; D053148:Caspase 3; D002945:Cisplatin
DUSP; MAPK protein phosphatase; Neuroprotection; Nucleotide receptor; P2Y(13) receptor; p38