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Neuronal release of soluble nucleotidases and their role in neurotransmitter inactivation

Nature volume 387, pages 76–79 (1997)Cite this article

Abstract

Efficient control of synaptic transmission requires a rapid mechanism for terminating the actions of neurotransmitters. For amino acids and monoamines, this is achieved by their uptake into the cell by specific high-affinity transporters1; acetylcholine is first broken down in the extracellular space and then choline is taken up by the cell2. Because ATP is hydrolysed to adenosine by membrane-bound enzymes (ectonucleotidases) that are present in most tissues3,4, it has been assumed that these enzymes terminate the neurotransmitter actions of ATP in the brain5 and in the periphery6,7. We show here, however, that stimulation of sympathetic nerves innervating the guinea-pig vas deferens releases not only neuronal ATP, but also soluble nucleotidases that break down this ATP to adenosine, indicating that inactivation of ATP is increased by nerve activity. This release of specific nucleotidases together with ATP represents a new mechanism for terminating the actions of a neurotransmitter.

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References

  1. Amara, S. G. & Kuhar, M. J. Neurotransporters: recent progress. Annu. Rev. Neurosci. 16, 73–93 (1993).

    Article  CAS  Google Scholar 

  2. Bowman, W. C. & Rand, M. J. Textbook of Pharmacology 2nd edn., 10.1–10.8 (Blackwell, Oxford, 1980).

    Google Scholar 

  3. Ziganshin, A. U., Hoyle, C. H. V. & Burnstock, G. Ecto-enzymes and metabolism of extracellular ATP. Drug Dev Res. 32, 134–146 (1994).

    Article  CAS  Google Scholar 

  4. Plesner, L. Ecto-ATPases: identities and functions. Int. J. Cytol. 158, 141–214 (1995).

    Article  CAS  Google Scholar 

  5. Edwards, F. A., Gibb, A. J. & Colquohoun, D. ATP receptor- mediated synaptic currents in the central nervous system. Nature 359, 144–146 (1992).

    Article  ADS  CAS  Google Scholar 

  6. Burnstock, G. Purinergic mechanisms . Annals NY Acad. Sci. 603, 1–17 (1990).

    Article  ADS  CAS  Google Scholar 

  7. Westfall, T. D., Kennedy, C. & Sneddon, P. Enhancement of sympathetic purinergic neurotransmission in the guinea-pig isolated vas deferens by the novel ecto ATPase inhibitor ARL 67156. Br. J. Pharmacol. 117 867–872 (1996).

    Article  CAS  Google Scholar 

  8. Sneddon, P., McLaren, G. J. & Kennedy, C. Purinergic cotransmission: sympathetic nerves. Semin. Neurosci. 8, 201–205 (1996).

    Article  CAS  Google Scholar 

  9. Gordon, J. Extracellular ATP: effects, sources and fate. Biochem. J. 233, 309–319 (1986).

    Article  CAS  Google Scholar 

  10. Kennedy, C. & Leff, P. How should P2x-purinoceptors be characterized pharmacologically? Trends Pharmacol. Sci. 16, 168–174 (1995).

    Article  CAS  Google Scholar 

  11. Pearson, J. D., Coade, S. B. & Cusack, N. J. Characterization of ectonucleotidases on vascular smooth muscle cells. Biochem. J. 230, 503–507 (1985).

    Article  CAS  Google Scholar 

  12. Welford, L. A., Cusack, N. J. & Hourani, S. M. O. ATP analogues and the guinea-pig taenia coli: a comparison of the structure activity relationships of ectonucleotidases with those of the P2-purinoceptor. Eur. J. Pharmacol. 129, 217–224 (1986).

    Article  CAS  Google Scholar 

  13. Welford, L. A. Cusack, N. J. & Hourani, S. M. O. The structure- activity relationships of ectonucleotidases and of excitatory P2-purinoceptors: evidence that dephosphorylation of ATP analogues reduces pharmacological potency. Eur J. Pharmacol. 141, 123–130 (1987).

    Article  CAS  Google Scholar 

  14. Todorov, L. D., Mihaylova-Todorova, S., Craviso, G. L., Bjur, R. A. & Westfall, D. P. Evidence for the differential release of the cotransmitters ATP and noradrenaline from sympathetic nerves of the guinea-pig vas deferens. J. Physiol.(Lond) 496, 731–748 (1996).

    Article  CAS  Google Scholar 

  15. Misumi, Y., Ogata, S., Hirose, S. & Ikehara, Y. Primary structure of rat liver 5' nucleotidase deduced from the cDNA. J. Biol. Chem. 265, 2178–2183 (1990).

    CAS  PubMed  Google Scholar 

  16. Misumi, Y., Ogata, S., Ohkubo, K. Hirose, S. & Ikehara, Y. Primary structure of human placental 5'- and identification of the glycolipid anchor in the mature form. Eur J. Biochem. 191, 563– 569, (1990).

    Article  CAS  Google Scholar 

  17. Crack, B. E. et al. Pharmacological and biochemical analysis of FPL 67156, a novel, selective inhibitor of ecto-ATPase . Br. J. Pharmacol. 114, 475–481 (1995).

    Article  CAS  Google Scholar 

  18. Khakh, B. S., Michel, A. D. & Humphrey, P. P. A. Inhibition of ectoATPase and Ca-ATPase in rat vas deferens by P2-purinoceptor antagonists . Br J. Pharmacol. 115, 2P (1995).

  19. Hourani, S. M. O. & Chown, J. A. The effects of some possible inhibitors of ectonucleotidases on the breakdown and pharmacological effects of ATP in the guinea-pig urinary Bladder. Gen. Pharmacol. 20, 413–416 (1989).

    Article  CAS  Google Scholar 

  20. Bailey, S. J. & Hourani, S. M. O. Differential effects of suramin on P2-purinoceptors mediating contraction of the guinea- pig vas deferens and urinary bladder. Br. J.Pharmacol. 112, 219–225 (1994).

    Article  CAS  Google Scholar 

  21. Stout, J. G. & Kirley, T. L. Inhibition of purified chicken gizzard smooth muscle ecto-ATPase by P2-antagonists. Biochem. Mol. Biol. Int. 36, 927–934 (1995).

    CAS  PubMed  Google Scholar 

  22. Schuldiner, S., Shirvan, A. & Linial, M. Vesicular neurotransmitter transporters: from bacteria to humans. Physiol. Rev. 95, 369–392 91995).

    Article  Google Scholar 

  23. Maliszewski, C. R. et al. The CD39 lymphoid cell activation antigen. Molecular cloning and structural characterization. J. Immunol. 153, 3574–3583 (1994).

    CAS  PubMed  Google Scholar 

  24. Bermudes, D., Ran Peck, K., Afifi Afifi, M., Beckers, C. J. M. & Joiner, K. A. Tandemly repeated genes encode nucleoside triphosphate hydrolase isoforms secreted into the parasitophorous vacuole of Toxoplasma gondii. J. Biol. Chem. 269, 29252–29260 (1994).

    CAS  PubMed  Google Scholar 

  25. Asai, T., Miura, S., Sibley, L. D., Okabayashi, H. & Tkeuchi, T. Biochemical and molecular characterization of nucleoside triphosphate hydrolase isozymes from the parasitic protozoan Toxoplasma gondii. J. Biol. Chem. 270, 11391–11397 (1995).

    Article  CAS  Google Scholar 

  26. Wang, T. F. Guidotti, G. CD39 is an ecto-(Ca2+Mg2+)-apyrase. J. Biol. Chem. 271, 9898–9901 (1996).

    Article  CAS  Google Scholar 

  27. Levitt, B., Head, R. J. & Westfall, D. P. High-pressure liquid chromotographic-fluorometric detection of ad- and adenine nucleotides: applications to endogenous content and electrically induced release of adenyl purines in guinea-pig vas deferens. Analyt. Biochem. 137, 93–100 (1984).

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Pharmacology, University of Nevada School of Medicine, Reno, Nevada, 89557, USA

    Latchezar D. Todorov, Svetlana Mihaylova-Todorova, Richard A. Bjur & David P. Westfall

  2. Department of Physiology and Pharmacology, University of Strathclyde, Royal College, 204 George Street, Glasgow, G1 1XW, UK

    Timothy D. Westfall, Peter Sneddon & Charles Kennedy

Authors
  1. Latchezar D. Todorov
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  2. Svetlana Mihaylova-Todorova
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  3. Timothy D. Westfall
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  4. Peter Sneddon
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  5. Charles Kennedy
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  6. Richard A. Bjur
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  7. David P. Westfall
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Todorov, L., Mihaylova-Todorova, S., Westfall, T. et al. Neuronal release of soluble nucleotidases and their role in neurotransmitter inactivation. Nature 387, 76–79 (1997). https://doi.org/10.1038/387076a0

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