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Molecular determinants of P2Y2 nucleotide receptor function

Implications for proliferative and inflammatory pathways in astrocytes

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Abstract

In the mammalian nervous system, P2 nucleotide receptors mediate neurotransmission, release of proinflammatory cytokines, and reactive astrogliosis. Extracellular nucleotides activate multiple P2 receptors in neurons and glial cells, including G protein-coupled P2Y receptors and P2X receptors, which are ligand-gated ion channels. In glial cells, the P2Y2 receptor subtype, distinguished by its ability to be equipotently activated by ATP and UTP, is coupled to pro-inflammatory signaling pathways. In situ hybridization studies with rodent brain slices indicate that P2Y2 receptors are expressed primarily in the hippocampus and cerebellum. Astrocytes express several P2 receptor subtypes, including P2Y2 receptors whose activation stimulates cell proliferation and migration. P2Y2 receptors, via an RGD (Arg-Gly-Asp) motif in their first extracellular loop, bind to αvβ3/β5 integrins, whereupon P2Y2 receptor activation stimulates integrin signaling pathways that regulate cytoskeletal reorganization and cell motility. The C-terminus of the P2Y2 receptor contains two Src-homology-3 (SH3)-binding domains that upon receptor activation, promote association with Src and transactivation of growth factor receptors. Together, our results indicate that P2Y2 receptors complex with both integrins and growth factor receptors to activate multiple signaling pathways. Thus, P2Y2 receptors present novel targets to control reactive astrogliosis in neurodegenerative diseases.

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Authors and Affiliations

  1. Department of Biochemistry and Neuroscience Program, University of Missouri-Columbia, Columbia, MO

    Gary A. Weisman, M. Wang, Q. Kong, Grace Y. Sun, C. I. Seye & L. Erb

  2. University of Puerto Rico, Rio Piedras, Puerto Rico

    N. E. Chorna & Fernando A. González

  3. Research Service, VA Medical Center and Departments of Pathology, Biochemistry, and Molecular Biology and Neuroscience Program, University of Miami School of Medicine, Miami, FL

    J. T. Neary

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  1. Gary A. Weisman
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  2. M. Wang
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  3. Q. Kong
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  4. N. E. Chorna
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  5. J. T. Neary
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  6. Grace Y. Sun
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  7. Fernando A. González
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  8. C. I. Seye
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  9. L. Erb
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Correspondence to Gary A. Weisman.

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Weisman, G.A., Wang, M., Kong, Q. et al. Molecular determinants of P2Y2 nucleotide receptor function. Mol Neurobiol 31, 169–183 (2005). https://doi.org/10.1385/MN:31:1-3:169

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  • DOI: https://doi.org/10.1385/MN:31:1-3:169

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