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Sphingosine 1-phosphate (S1P) regulates vascular contraction via S1P3 receptor: investigation based on a new S1P3 receptor antagonist.

Authors
  • Murakami, Akira
  • Takasugi, Hiroshi
  • Ohnuma, Shinya
  • Koide, Yuuki
  • Sakurai, Atsuko
  • Takeda, Satoshi
  • Hasegawa, Takeshi
  • Sasamori, Jun
  • Konno, Takashi
  • Hayashi, Kenji
  • Watanabe, Yoshiaki
  • Mori, Koji
  • Sato, Yoshimichi
  • Takahashi, Atsuo
  • Mochizuki, Naoki
  • Takakura, Nobuyuki
Type
Published Article
Journal
Molecular Pharmacology
Publisher
American Society for Pharmacology & Experimental Therapeutics
Publication Date
Apr 01, 2010
Volume
77
Issue
4
Pages
704–713
Identifiers
DOI: 10.1124/mol.109.061481
PMID: 20097776
Source
Medline
License
Unknown

Abstract

Sphingosine 1-phosphate (S1P) induces diverse biological responses in various tissues by activating specific G protein-coupled receptors (S1P(1)-S1P(5) receptors). The biological signaling regulated by S1P(3) receptor has not been fully elucidated because of the lack of an S1P(3) receptor-specific antagonist or agonist. We developed a novel S1P(3) receptor antagonist, 1-(4-chlorophenylhydrazono)-1-(4-chlorophenylamino)-3,3-dimethyl- 2-butanone (TY-52156), and show here that the S1P-induced decrease in coronary flow (CF) is mediated by the S1P(3) receptor. In functional studies, TY-52156 showed submicromolar potency and a high degree of selectivity for S1P(3) receptor. TY-52156, but not an S1P(1) receptor antagonist [(R)-phosphoric acid mono-[2-amino-2-(3-octyl-phenylcarbamoyl)-ethyl] ester; VPC23019] or S1P(2) receptor antagonist [1-[1,3-dimethyl-4-(2-methylethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl]-4-(3,5-dichloro-4-pyridinyl)-semicarbazide; JTE013], inhibited the decrease in CF induced by S1P in isolated perfused rat hearts. We further investigated the effect of TY-52156 on both the S1P-induced increase in intracellular calcium ([Ca(2+)](i)) and Rho activation that are responsible for the contraction of human coronary artery smooth muscle cells. TY-52156 inhibited both the S1P-induced increase in [Ca(2+)](i) and Rho activation. In contrast, VPC23019 and JTE013 inhibited only the increase in [Ca(2+)](i) and Rho activation, respectively. We further confirmed that TY-52156 inhibited FTY-720-induced S1P(3) receptor-mediated bradycardia in vivo. These results clearly show that TY-52156 is both sensitive and useful as an S1P(3) receptor-specific antagonist and reveal that S1P induces vasoconstriction by directly activating S1P(3) receptor and through a subsequent increase in [Ca(2+)](i) and Rho activation in vascular smooth muscle cells.

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