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Extracellular ATP Selectively Upregulates Ecto-Nucleoside Triphosphate Diphosphohydrolase 2 and Ecto-5′-Nucleotidase by Rat Cortical Astrocytes In Vitro

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Abstract

Extracellular ATP (eATP) acts as a danger-associated molecular pattern which induces reactive response of astrocytes after brain insult, including morphological remodeling of astrocytes, proliferation, chemotaxis, and release of proinflammatory cytokines. The responses induced by eATP are under control of ecto-nucleotidases, which catalyze sequential hydrolysis of ATP to adenosine. In the mammalian brain, ecto-nucleotidases comprise three enzyme families: ecto-nucleoside triphosphate diphosphohydrolases 1–3 (NTPDase1–3), ecto-nucleotide pyrophosphatase/phospodiesterases 1–3 (NPP1–3), and ecto-5′-nucleotidase (eN), which crucially determine ATP/adenosine ratio in the pericellular milieu. Altered expression of ecto-nucleotidases has been demonstrated in several experimental models of human brain dysfunctions. In the present study, we have explored the pattern of NTPDase1–3, NPP1–3, and eN expression by cultured cortical astrocytes challenged with 1 mmol/L ATP (eATP). At the transcriptional level, eATP upregulated expression of NTPDase1, NTPDase2, NPP2, and eN, while, at translational and functional levels, these were paralleled only by the induction of NTPDase2 and eN. Additionally, eATP altered membrane topology of eN, from clusters localized in membrane domains to continuous distribution along the cell membrane. Our results suggest that eATP, by upregulating NTPDase2 and eN and altering the enzyme membrane topology, affects local kinetics of ATP metabolism and signal transduction that may have important roles in the process related to inflammation and reactive gliosis.

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Acknowledgments

This work was supported by Serbian Ministry for Education and Science Project No. III41014 and Bilateral Project between DAAD and Serbian Ministry of Education and Science. DB was supported by DAAD financed Scientific Internship in Germany for Undergraduates and Graduates from Serbia.

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Authors and Affiliations

  1. Institute for Physiology and Biochemistry, Faculty of Biology, University of Belgrade, Studentski trg 3, Belgrade, 11001, Serbia

    Dusica Brisevac, Marija Adzic, Danijela Laketa, Milena Milosevic & Nadezda Nedeljkovic

  2. Center for Laser Microscopy, Faculty of Biology, University of Belgrade, Belgrade, Serbia

    Marija Adzic & Milena Milosevic

  3. Institute for Biological Research “Sinisa Stankovic”, University of Belgrade, Belgrade, Serbia

    Ana Parabucki, Irena Lavrnja & Ivana Bjelobaba

  4. Département de microbiologie-infectiologie et d’immunologie, Faculté de Médecine, Université Laval, Québec, QC, G1V 0A6, Canada

    Jean Sévigny

  5. Centre de recherche du CHU de Québec Université Laval, Québec, QC, G1V 4G2, Canada

    Jean Sévigny

  6. Institute of Neuroanatomy, Faculty of Medicine, RWTH Aachen University, Aachen, Germany

    Markus Kipp

  7. Department of Anatomy II, Ludwig-Maximilians-University of Munich, Munich, Germany

    Markus Kipp

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  1. Dusica Brisevac
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  2. Marija Adzic
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Brisevac, D., Adzic, M., Laketa, D. et al. Extracellular ATP Selectively Upregulates Ecto-Nucleoside Triphosphate Diphosphohydrolase 2 and Ecto-5′-Nucleotidase by Rat Cortical Astrocytes In Vitro. J Mol Neurosci 57, 452–462 (2015). https://doi.org/10.1007/s12031-015-0601-y

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