Identification and characterization of a cell-surface receptor, P2Y15, for AMP and adenosine

AMP and adenosine are found in all cell types and can be released by cells or created extracellularly from the breakdown of ATP and ADP. We have identified an orphan G protein-coupled receptor with homology to the P2Y family of nucleotide receptors that can respond to both AMP and adenosine. Based on its ability to functionally bind the nucleotide AMP, we have named it P2Y15. Upon stimulation, P2Y15 induces both Ca2+ mobilization and cyclic AMP generation, suggesting coupling to at least two different G proteins. It is highly expressed in mast cells and is found predominantly in the tissues of the respiratory tract and kidneys, which are known to be affected by AMP, adenosine, and adenosine antagonists. Until now, the effects of AMP have been thought to depend on its dephosphorylation to adenosine but we demonstrate here that P2Y15 is a bona fide AMP receptor by showing that it binds [(32)P]AMP. Because AMP and adenosine have bronchoconstrictive effects that can be inhibited by theophylline, we tested whether theophylline and other adenosine receptor antagonists can block P2Y15. We found inhibition at a theophylline concentration well within the therapeutic dose range, indicating that P2Y15 may be a clinically important target of this drug.