Extended pharmacological profiles of rat P2Y 2 and rat P2Y 4 receptors and their sensitivity to extracellular H + and Zn 2+ ions

Two molecularly distinct rat P2Y receptors activated equally by adenosine‐5′‐triphosphate (ATP) and uridine‐5′‐triphosphate (UTP) (rP2Y 2 and rP2Y 4 receptors) were expressed in Xenopus oocytes and studied extensively to find ways to pharmacologically distinguish one from the other. Both P2Y subtypes were activated fully by a number of nucleotides. Tested nucleotides were equipotent at rP2Y 4 (ATP=UTP=CTP=GTP=ITP), but not at rP2Y 2 (ATP=UTP>CTP>GTP>ITP). For dinucleotides (Ap n A, n =2–6), rP2Y 4 was only fully activated by Ap 4 A, which was as potent as ATP. All tested dinucleotides, except for Ap 2 A, fully activated rP2Y 2 , but none were as potent as ATP. ATP γ S and BzATP fully activated rP2Y 2 , whereas ATP γ S was a weak agonist and BzATP was inactive (as an agonist) at rP2Y 4 receptors. Each P2Y subtype showed different sensitivities to known P2 receptor antagonists. For rP2Y 2 , the potency order was suramin>>PPADS= RB‐2>TNP‐ATP and suramin was a competitive antagonist (pA 2 , 5.40). For rP2Y 4 , the order was RB‐2>>suramin>PPADS> TNP‐ATP and RB‐2 was a competitive antagonist (pA 2 , 6.43). Also, BzATP was an antagonist at rP2Y 4 receptors. Extracellular acidification (from pH 8.0 to pH 5.5) enhanced the potency of ATP and UTP by 8–10‐fold at rP2Y 4 but did not affect agonist responses at rP2Y 2 receptors. Extracellular Zn 2+ ions (0.1–300 μ M ) coapplied with ATP inhibited agonist responses at rP2Y 4 but not at rP2Y 2 receptors. These two P2Y receptors differ significantly in terms of agonist and antagonist profiles, and the modulatory activities of extracellular H + and Zn 2+ ions. These pharmacological differences will help to distinguish between rP2Y 2 and rP2Y 4 receptors, in vivo .British Journal of Pharmacology (2003) 140 , 1177–1186. doi: 10.1038/sj.bjp.0705544