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J. Biol. Chem., Vol. 277, Issue 10, 7761-7765, March 8, 2002

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P2Y₁₁ Receptors Activate Adenylyl Cyclase and Contribute to Nucleotide-promoted cAMP Formation in MDCK-D₁ Cells
A MECHANISM FOR NUCLEOTIDE-MEDIATED AUTOCRINE-PARACRINE REGULATION^*

Brian Torres, Alexander C. Zambon, and Paul A. Insel

From the Department of Pharmacology, University of California, San Diego, La Jolla, California 92093-0636

Extracellular nucleotides activate P2Y receptors, thereby increasing cAMP formation in Madin-Darby canine kidney (MDCK-D₁) cells, which express P2Y₁, P2Y₂, and P2Y₁₁ receptors (Post, S. R., Rump, L. C., Zambon, A., Hughes, R. J., Buda, M. D., Jacobson, J. P., Kao, C. C., and Insel, P. A. (1998) J. Biol. Chem. 273, 23093-23097). The cyclooxygenase inhibitor indomethacin (indo) eliminates UTP-promoted cAMP formation (i.e. via P2Y₂ receptors) but only partially blocks ATP-promoted cAMP formation. The latter response is completely blocked by the nonselective P2Y receptor antagonist suramin. We have sought to identify the mechanism for this P2Y receptor-mediated, indo-resistant cAMP formation. The agonist rank order potencies for cAMP formation were: ADPS  MT-ADP > 2-MT-ATP > ADP, ATP, ATPS > UTP, AMP, adenosine. We found a similar rank order in MDCK-D₁ cells overexpressing cloned green fluorescent protein-tagged P2Y₁₁ receptors, but the potency of the agonists was enhanced, consistent with a P2Y₁₁ receptor-mediated effect. cAMP generation by the P2Y₁ and P2Y₁₁ receptor agonist ADPS was not inhibited by several P2Y₁-selective antagonists (PPADS, A2P5P, and MRS 2179). Forskolin synergistically enhanced cAMP generation in response to ADPS or PGE₂, implying that, like PGE₂, ADPS activates adenylyl cyclase via G_s, a conclusion supported by results showing ADPS and MT-ADP promoted activation of adenylyl cyclase activity in MDCK-D₁ membranes. We conclude that nucleotide-promoted, indo-resistant cAMP formation in MDCK-D₁ cells occurs via G_s-linked P2Y₁₁ receptors. These data describing adenylyl cyclase activity via endogenous P2Y₁₁ receptors define a mechanism by which released nucleotides can increase cAMP in MDCK-D₁ and other P2Y₁₁-containing cells.

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