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Cell signaling via the P2X7 nucleotide receptor: linkage to ROS production, gene transcription, and receptor trafficking

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Abstract

Extracellular nucleotides can act as important intercellular signals in diverse biological processes, including the enhanced production of factors that are key to immune response regulation. One receptor that binds extracellular adenosine triphosphate released at sites of infection and injury is P2X7, which is an ionotrophic receptor that can also lead to the formation of a non-specific pore, activate multiple mitogen-activated protein kinases (MAPKs), and stimulate the production of immune mediators including interleukin family members and reactive oxygen species (ROS). In the present report, we have investigated the signaling mechanisms by which P2X7 promotes monocytic cell mediator production and induces transcription factor expression/phosphorylation, as well as how receptor-associated pore activity is regulated by intracellular trafficking. We report that P2X7 stimulates ROS production in macrophages through the MAPKs ERK1/2 and the nicotinamide adenine dinucleotide phosphate oxidase complex, activates several transcription factors including cyclic-AMP response element-binding protein and components of the activating protein-1 complex, and contains specific sequences within its intracellular C-terminus that appear critical for its activity. Altogether, these data further implicate P2X7 activation and signaling as a fundamental modulator of macrophage immune responses.

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Acknowledgments

We thank Drs. Mary Ellen Bates and Greg Wiepz for critical comments about the manuscript. This work was supported by National Institutes of Health (NIH) grants 1 U19 AI070503, 2 R01 HL069116, and 1 P01 HL0885940 to PJB, a Hartwell Foundation postdoctoral fellowship to LYL, NIH Molecular & Cellular Pharmacology Training Grant T32 GM008688 to LMH, and NIH Hematology Training Grant T32 HL07899 to MLG.

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  1. Department of Biomolecular Chemistry, University of Wisconsin-Madison, Madison, WI, 53706, USA

    Lisa Y. Lenertz, Monica L. Gavala, Lindsay M. Hill & Paul J. Bertics

  2. University of Wisconsin School of Medicine and Public Health, 571A Medical Sciences Center, 1300 University Avenue, Madison, WI, 53706, USA

    Paul J. Bertics

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  1. Lisa Y. Lenertz
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  2. Monica L. Gavala
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Lenertz, L.Y., Gavala, M.L., Hill, L.M. et al. Cell signaling via the P2X7 nucleotide receptor: linkage to ROS production, gene transcription, and receptor trafficking. Purinergic Signalling 5, 175–187 (2009). https://doi.org/10.1007/s11302-009-9133-7

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