Original paper

Purinergic Signalling

, Volume 1, Issue 2, pp 193-204

Open Access This content is freely available online to anyone, anywhere at any time.

Comparative hydrolysis of P2 receptor agonists by NTPDases 1, 2, 3 and 8

  • F. KukulskiAffiliated withCentre de recherche en Rhumatologie et Immunologie, Centre hospitalier de l’Université Laval
  • , S. A. LévesqueAffiliated withCentre de recherche en Rhumatologie et Immunologie, Centre hospitalier de l’Université Laval
  • , É. G. LavoieAffiliated withCentre de recherche en Rhumatologie et Immunologie, Centre hospitalier de l’Université Laval
  • , J. LeckaAffiliated withCentre de recherche en Rhumatologie et Immunologie, Centre hospitalier de l’Université Laval
  • , F. BigonnesseAffiliated withCentre de recherche en Rhumatologie et Immunologie, Centre hospitalier de l’Université Laval
  • , A. F. KnowlesAffiliated withDepartment of Chemistry and Biochemistry, San Diego State University
  • , S. C. RobsonAffiliated withDepartment of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School
  • , T. L. KirleyAffiliated withDepartment of Pharmacology and Cell Biophysics, College of Medicine, University of Cincinnati
  • , J. SévignyAffiliated withCentre de recherche en Rhumatologie et Immunologie, Centre hospitalier de l’Université LavalCentre de recherche en Rhumatologie et Immunologie, Centre hospitalier de l’Université Laval Email author 

Abstract

Nucleoside triphosphate diphosphohydrolases 1, 2, 3 and 8 (NTPDases 1, 2, 3 and 8) are the dominant ectonucleotidases and thereby expected to play important roles in nucleotide signaling. Distinct biochemical characteristics of individual NTPDases should allow them to regulate P2 receptor activation differentially. Therefore, the biochemical and kinetic properties of these enzymes were compared. NTPDases 1, 2, 3 and 8 efficiently hydrolyzed ATP and UTP with K m values in the micromolar range, indicating that they should terminate the effects exerted by these nucleotide agonists at P2X1- and P2Y2,4,11 receptors. Since NTPDase1 does not allow accumulation of ADP, it should terminate the activation of P2Y1,12,13 receptors far more efficiently than the other NTPDases. In contrast, NTPDases 2, 3 and 8 are expected to promote the activation of ADP specific receptors, because in the presence of ATP they produce a sustained (NTPDase2) or transient (NTPDases 3 and 8) accumulation of ADP. Interestingly, all plasma membrane NTPDases dephosphorylate UTP with a significant accumulation of UDP, favoring P2Y6 receptor activation. NTPDases differ in divalent cation and pH dependence, although all are active in the pH range of 7.0-.5. Various NTPDases may also distinctly affect formation of extracellular adenosine and therefore adenosine receptor-mediated responses, since they generate different amounts of the substrate (AMP) and inhibitor (ADP) of ecto-5-nucleotidase, the rate limiting enzyme in the production of adenosine. Taken together, these data indicate that plasma membrane NTPDases hydrolyze nucleotides in a distinctive manner and may therefore differentially regulate P2 and adenosine receptor signaling.

Key words

ATP ATPase ectonucleotidase extracellular nucleotide Pl receptor P2 receptor