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J Biol Chem, Vol. 273, Issue 36, 23093-23097, September 4, 1998

ATP Activates cAMP Production via Multiple Purinergic Receptors in MDCK-D1 Epithelial Cells
BLOCKADE OF AN AUTOCRINE/PARACRINE PATHWAY TO DEFINE RECEPTOR PREFERENCE OF AN AGONIST

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

Extracellular nucleotides regulate function in many cell types via activation of multiple P₂-purinergic receptor subtypes. However, it has been difficult to define which individual subtypes mediate responses to the physiological agonist ATP. We report a novel means to determine this by exploiting the differential activation of an autocrine/paracrine signaling pathway. We used Madin-Darby canine kidney epithelial cells (MDCK-D1) and assessed the regulation of cAMP formation by nucleotides. We found that ATP, 2-methylthio-ATP (MT-ATP) and UTP increase cAMP production. The cyclooxygenase inhibitor indomethacin completely inhibited UTP-stimulated, did not inhibit MT-ATP-stimulated, and only partially blocked ATP-stimulated cAMP formation. In parallel studies, ATP and UTP but not MT-ATP stimulated prostaglandin production. By pretreating cells with indomethacin to eliminate the P_2Y2/prostaglandin component of cAMP formation, we could assess the indomethacin-insensitive P₂ receptor component. Under these conditions, ATP displayed a ten-fold lower potency for stimulation of cAMP formation compared with untreated cells. These data indicate that ATP preferentially activates P_2Y2 relative to other P₂ receptors in MDCK-D1 cells (P_2Y1 and P_2Y11, as shown by reverse transcriptase polymerase chain reaction) and that P_2Y2 receptor activation is the principal means by which ATP increases cAMP formation in these cells. Blockade of autocrine/paracrine signaling can aid in dissecting the contribution of multiple receptor subtypes activated by an agonist.

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