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P2Y 2 receptors activate neuroprotective mechanisms in astrocytic cells
Author(s) -
Chortaliya E.,
SantiagoPérez Laura I.,
Erb Laurie,
Seye Cheikh I.,
Neary Joseph T.,
Sun Grace Y.,
Weisman Gary A.,
González Fernando A.
Publication year - 2004
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2004.02699.x
Subject(s) - receptor , p2y receptor , microbiology and biotechnology , biology , neuroprotection , ppads , neurite , signal transduction , neurotrophin , purinergic receptor , extracellular , biochemistry , pharmacology , in vitro
Mechanical or ischemic trauma to the CNS causes the release of nucleotides and other neurotransmitters into the extracellular space. Nucleotides can activate nucleotide receptors that modulate the expression of genes implicated in cellular adaptive responses. In this investigation, we used human 1321N1 astrocytoma cells expressing a recombinant P2Y 2 receptor to assess the role of this receptor in the regulation of anti‐apoptotic ( bcl‐2 and bcl‐xl ) and pro‐apoptotic ( bax ) gene expression. Acute treatment with the P2Y 2 receptor agonist UTP up‐regulated bcl‐2 and bcl‐xl , and down‐regulated bax , gene expression. Activation of P2Y 2 receptors was also coupled to the phosphorylation of cyclic AMP responsive element binding protein that positively regulates bcl‐2 and bcl‐xl gene expression. Cyclic AMP responsive element decoy oligonucleotides markedly attenuated the UTP‐induced increase in bcl‐2 and bcl‐xl mRNA levels. Activation of P2Y 2 receptors induced the phosphorylation of the pro‐apoptotic factor Bad and caused a reduction in bax/bcl‐2 mRNA expression ratio. All these signaling pathways are known to be involved in cell survival mechanisms. Using cDNA microarray analysis and RT–PCR, P2Y 2 receptors were found to up‐regulate the expression of genes for neurotrophins, neuropeptides and growth factors including nerve growth factor 2; neurotrophin 3; glia‐derived neurite‐promoting factor, as well as extracellular matrix proteins CD44 and fibronectin precursor – genes known to regulate neuroprotection. Consistent with this observation, conditioned media from UTP‐treated 1321N1 cells expressing P2Y 2 receptors stimulated the outgrowth of neurites in PC‐12 cells. Taken together, our results suggest an important novel role for the P2Y 2 receptor in survival and neuroprotective mechanisms under pathological conditions.