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Biomedical Research

Signal transduction pathways for P2Y2 and P2X7 nucleotide receptors that mediate neuroinflammatory responses in astrocytes and microglial cells

Author(s): Fernand-Pierre Gendron, Nathan L. Newbold, Pablo E. Vivas-Mejia, Min Wang, Joseph T. Neary, Grace Y. Sun, Fernando A. Gonzalez, and Gary A. Weisman

Vol. 14, No. 1 (2003-01 - 2003-06)

Fernand-Pierre Gendron, Nathan L. Newbold, Pablo E. Vivas-Mejia, Min Wang, Joseph T. Neary, Grace Y. Sun, Fernando A. Gonzalez, and Gary A. Weisman

Correspondence to:

Dr. Gary A. Weisman
University of Missouri-Columbia
Department of Biochemistry
M121 Medical Sciences Building
Columbia, MO 65212 USA

Phone: (573) 882-5005
Fax: (573) 884-4597
e-mail: weismang(at)

Inflammation is a major factor in brain damage associated with neurodegenerative disorders, such as Alzheimer’s disease. Immunoreactive microglial cells and astrocytes play important roles in inflammation in the brain. Under normal and pathological conditions, cells in the central nervous system release nucleotides that regulate a wide range of cellular responses via cell-surface P2 nucleotide receptors. Several P2 receptor subtypes, including the G protein-coupled P2Y2 receptor and the P2X7 receptor, a ligand-gated ion channel, are expressed in glial cells where they have been proposed to activate signaling pathways that mediate inflammatory responses. In this study, we have shown that primary rat astrocytes treated with extracellular nucleotides release arachidonic acid, a substrate for pro-inflammatory mediators generated by cyclooxygenase. Immortalized DITNC astrocytes treated with the P2Y2 receptor agonist UTP exhibited increased expression of mRNA to TGF-b, an inflammatory growth factor. Other results indicate that UTP induces phosphorylation of the stress-activated protein kinases, p38 and JNK1/3. UTP-induced TGF-b mRNA expression was prevented by inhibition of p38, suggesting the involvement of this signaling molecule in TGF-b expression. In addition to the activation of p38 and JNK1/3, P2Y2 and P2X7 receptors (P2Y2-R; P2X7-R) in astrocytes and P2Y2-R in BV-2 microglial cells also activate another member of the mitogen-activated protein kinase (MAPK) family, ERK1/2. Phosphorylation of ERK1/2 induced by the P2Y2 receptor agonists ATP or UTP in DITNC astrocytes was partially dependent on increases in the intracellular calcium concentration and the activities of protein kinase C (PKC), and c-Src, since P2Y2 receptor-mediated ERK1/2 activation was partially inhibited by the intracellular calcium chelator, BAPTA, the non-specific PKC inhibitor GF109203X, and the c-Src inhibitor PP2, respectively. In contrast, ERK1/2 phosphorylation in BV-2 microglial cells treated with ATP or UTP was calcium-independent, required the activation of PI 3-kinase and was partially dependent on c-Src and PKC. In primary cultures of rat cortical astrocytes, ERK1/2 phosphorylation is coupled to the activation of P2Y2 and P2X7 receptors and was partially dependent on calcium entry and PKC activity. Taken together, our results indicate that both P2Y2 and P2X7 receptors in glial cells activate several MAPKs that contribute to inflammation and other glial cell responses, although the interrelationship of these receptor-signaling pathways remains to be determined.

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