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1 Department of Biochemistry, University of Missouri-Columbia, Columbia, Missouri 65212; 2 Research Service, Veterans Affairs Medical Center, Departments of Pathology, Biochemistry and Molecular Biology, and the Neuroscience Program, University of Miami School of Medicine, Miami, Florida 33125; and 3 Department of Chemistry, University of Puerto Rico, Rio Piedras, Puerto Rico 00931
Astrocytes are involved in normal and
pathological brain functions, where they become activated and undergo
reactive gliosis. Astrocytes have been shown to respond to
extracellular nucleotides via the activation of P2 receptors, either G
protein-coupled P2Y receptors or P2X receptors that are ligand-gated
ion channels. In this study, we have examined the manner in which
activation of the P2X7 nucleotide receptor, an
extracellular ATP-gated ion channel expressed in astrocytes, can lead
to the phosphorylation of ERK1/2. Results showed that the
P2X7 receptor agonist
2',3'-O-(4-benzoyl)benzoyl-ATP induced ERK1/2
phosphorylation in human astrocytoma cells overexpressing the
recombinant rat P2X7 receptor (rP2X7-R), a
response that was inhibited by the P2X7 receptor
antagonist, oxidized ATP. Other results suggest that
rP2X7-R-mediated ERK1/2 phosphorylation was linked to the
phosphorylation of the proline-rich/Ca2+-activated tyrosine
kinase Pyk2, c-Src, phosphatidylinositol 3'-kinase, and protein
kinase C
activities and was dependent on the presence of
extracellular Ca2+. These results support the hypothesis
that the P2X7 receptor and its signaling pathways play a
role in astrocyte-mediated inflammation and neurodegenerative disease.
astrocytes; P2 nucleotide receptors; ligand-gated ion channels; protein kinase C; mitogen-activated protein kinases
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