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Regulation of P2Y₁ Receptor-Mediated Signaling by the Ectonucleoside Triphosphate Diphosphohydrolase Isozymes NTPDase1 and NTPDase2

Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, North Carolina (C.A.-C., T.K.H. J.L.B.); and Inspire Pharmaceuticals Inc., Durham, North Carolina (J.L.B.)

Ectonucleoside triphosphate diphosphohydrolases (NTPDases) control the concentration of released extracellular nucleotides, but the precise physiological roles played by these isozymes in modulation of P2 receptor signaling remain unclear. Activation of the human P2Y₁ receptor was studied in the presence of NTPDase1 or NTPDase2 expressed either in the same cell as the receptor or in P2Y₁ receptor-expressing cells cocultured with NTPDaseexpressing cells. Coexpression of NTPDase1 with the P2Y₁ receptor resulted in increases in the EC₅₀ for 2'-methylthioadenosine 5'-diphosphate (2MeSADP; 12-fold), ADP (50-fold), and ATP (10-fold) for activation of phospholipase C. Similar effects were observed when the P2Y₁ receptor and NTPDase1 were expressed on different cells. These results are explained by the capacity of NTPDase1 to hydrolyze both nucleoside triphosphates and diphosphates. NTPDase2 preferentially hydrolyzes nucleoside triphosphates, and the presence of NTPDase2 under either coexpression or coculture conditions did not change the EC₅₀ of 2MeSADP, ADP, or adenosine 5'-O-(2-thiodiphosphate) for activation of the P2Y₁ receptor. However, the EC₅₀ for ATP was 15-fold lower in the presence of NTPDase2 than in cells expressing the P2Y₁ receptor alone. Whereas expression of NTPDase1 decreased basal activity of the P2Y₁ receptor, the presence of the NTPDase2 resulted in P2Y₁ receptor-dependent increases in basal activity. These results suggest that basal activity of the P2Y₁ receptor is maintained by paracrine or autocrine release of receptor agonists and that the biological and/or pharmacological response mediated by P2Y receptors in target tissues is highly dependent on the types of ectonucleotidases expressed in the vicinity of the receptor.

Received for publication September 2, 2004.

Accepted for publication October 19, 2004.

Address correspondence to: T. Kendall Harden, Department of Pharmacology, University of North Carolina School of Medicine, CB#7365, Chapel Hill, NC 27599-7365. E-mail: tkh{at}med.unc.edu

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