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

Extended pharmacological profiles of rat P2Y 2 and rat P2Y 4 receptors and their sensitivity to... Two molecularly distinct rat P2Y receptors activated equally by adenosine‐5′‐triphosphate (ATP) and uridine‐5′‐triphosphate (UTP) (rP2Y2 and rP2Y4 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 rP2Y4 (ATP=UTP=CTP=GTP=ITP), but not at rP2Y2 (ATP=UTP>CTP>GTP>ITP). For dinucleotides (ApnA, n=2–6), rP2Y4 was only fully activated by Ap4A, which was as potent as ATP. All tested dinucleotides, except for Ap2A, fully activated rP2Y2, but none were as potent as ATP. ATPγS and BzATP fully activated rP2Y2, whereas ATPγS was a weak agonist and BzATP was inactive (as an agonist) at rP2Y4 receptors. Each P2Y subtype showed different sensitivities to known P2 receptor antagonists. For rP2Y2, the potency order was suramin>>PPADS= RB‐2>TNP‐ATP and suramin was a competitive antagonist (pA2, 5.40). For rP2Y4, the order was RB‐2>>suramin>PPADS> TNP‐ATP and RB‐2 was a competitive antagonist (pA2, 6.43). Also, BzATP was an antagonist at rP2Y4 receptors. Extracellular acidification (from pH 8.0 to pH 5.5) enhanced the potency of ATP and UTP by 8–10‐fold at rP2Y4 but did not affect agonist responses at rP2Y2 receptors. Extracellular Zn2+ ions (0.1–300 μM) coapplied with ATP inhibited agonist responses at rP2Y4 but not at rP2Y2 receptors. These two P2Y receptors differ significantly in terms of agonist and antagonist profiles, and the modulatory activities of extracellular H+ and Zn2+ ions. These pharmacological differences will help to distinguish between rP2Y2 and rP2Y4 receptors, in vivo. British Journal of Pharmacology (2003) 140, 1177–1186. doi:10.1038/sj.bjp.0705544 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png British Journal of Pharmacology Wiley

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

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References (45)

Publisher
Wiley
Copyright
2003 British Pharmacological Society
ISSN
0007-1188
eISSN
1476-5381
DOI
10.1038/sj.bjp.0705544
pmid
14581177
Publisher site
See Article on Publisher Site

Abstract

Two molecularly distinct rat P2Y receptors activated equally by adenosine‐5′‐triphosphate (ATP) and uridine‐5′‐triphosphate (UTP) (rP2Y2 and rP2Y4 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 rP2Y4 (ATP=UTP=CTP=GTP=ITP), but not at rP2Y2 (ATP=UTP>CTP>GTP>ITP). For dinucleotides (ApnA, n=2–6), rP2Y4 was only fully activated by Ap4A, which was as potent as ATP. All tested dinucleotides, except for Ap2A, fully activated rP2Y2, but none were as potent as ATP. ATPγS and BzATP fully activated rP2Y2, whereas ATPγS was a weak agonist and BzATP was inactive (as an agonist) at rP2Y4 receptors. Each P2Y subtype showed different sensitivities to known P2 receptor antagonists. For rP2Y2, the potency order was suramin>>PPADS= RB‐2>TNP‐ATP and suramin was a competitive antagonist (pA2, 5.40). For rP2Y4, the order was RB‐2>>suramin>PPADS> TNP‐ATP and RB‐2 was a competitive antagonist (pA2, 6.43). Also, BzATP was an antagonist at rP2Y4 receptors. Extracellular acidification (from pH 8.0 to pH 5.5) enhanced the potency of ATP and UTP by 8–10‐fold at rP2Y4 but did not affect agonist responses at rP2Y2 receptors. Extracellular Zn2+ ions (0.1–300 μM) coapplied with ATP inhibited agonist responses at rP2Y4 but not at rP2Y2 receptors. These two P2Y receptors differ significantly in terms of agonist and antagonist profiles, and the modulatory activities of extracellular H+ and Zn2+ ions. These pharmacological differences will help to distinguish between rP2Y2 and rP2Y4 receptors, in vivo. British Journal of Pharmacology (2003) 140, 1177–1186. doi:10.1038/sj.bjp.0705544

Journal

British Journal of PharmacologyWiley

Published: Dec 1, 2003

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