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Molecular Pharmacology

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Research ArticleArticle

Sphingosine 1-Phosphate (S1P) Regulates Vascular Contraction via S1P3 Receptor: Investigation Based on a New S1P3 Receptor Antagonist

Akira Murakami, Hiroshi Takasugi, Shinya Ohnuma, Yuuki Koide, Atsuko Sakurai, Satoshi Takeda, Takeshi Hasegawa, Jun Sasamori, Takashi Konno, Kenji Hayashi, Yoshiaki Watanabe, Koji Mori, Yoshimichi Sato, Atsuo Takahashi, Naoki Mochizuki and Nobuyuki Takakura
Molecular Pharmacology April 2010, 77 (4) 704-713; DOI: https://doi.org/10.1124/mol.109.061481
Akira Murakami
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Hiroshi Takasugi
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Shinya Ohnuma
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Yuuki Koide
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Atsuko Sakurai
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Satoshi Takeda
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Takeshi Hasegawa
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Jun Sasamori
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Takashi Konno
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Kenji Hayashi
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Yoshiaki Watanabe
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Koji Mori
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Yoshimichi Sato
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Atsuo Takahashi
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Naoki Mochizuki
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Nobuyuki Takakura
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Abstract

Sphingosine 1-phosphate (S1P) induces diverse biological responses in various tissues by activating specific G protein-coupled receptors (S1P1–S1P5 receptors). The biological signaling regulated by S1P3 receptor has not been fully elucidated because of the lack of an S1P3 receptor-specific antagonist or agonist. We developed a novel S1P3 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 S1P3 receptor. In functional studies, TY-52156 showed submicromolar potency and a high degree of selectivity for S1P3 receptor. TY-52156, but not an S1P1 receptor antagonist [(R)-phosphoric acid mono-[2-amino-2-(3-octyl-phenylcarbamoyl)-ethyl] ester; VPC23019] or S1P2 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 ([Ca2+]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 [Ca2+]i and Rho activation. In contrast, VPC23019 and JTE013 inhibited only the increase in [Ca2+]i and Rho activation, respectively. We further confirmed that TY-52156 inhibited FTY-720-induced S1P3 receptor-mediated bradycardia in vivo. These results clearly show that TY-52156 is both sensitive and useful as an S1P3 receptor-specific antagonist and reveal that S1P induces vasoconstriction by directly activating S1P3 receptor and through a subsequent increase in [Ca2+]i and Rho activation in vascular smooth muscle cells.

Footnotes

    fn-1
  • ↵Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

  • fn-2
  • This work was supported by Research on Health Science Focusing on Drug Innovation from the Japan Health Sciences Foundation [Grant KHC1016].

  • fn-3
  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.109.061481.

  • fn-4
  • ABBREVIATIONS:

    S1P
    sphingosine 1-phosphate
    GPCR
    G protein-coupled receptor
    TY-52156
    1-(4-chlorophenylhydrazono)-1-(4-chlorophenylamino)-3,3-dimethyl-2-butanone
    MAPK
    mitogen-activated protein kinase
    CF
    coronary flow
    HUVEC
    human umbilical vein endothelial cell
    HCASMC
    human coronary artery smooth muscle cell
    SBP
    systemic blood pressure
    HR
    heart rate
    MBP
    mean blood pressure
    JTE013
    1-[1,3-dimethyl-4-(2-methylethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl]-4-(3,5-dichloro-4-pyridinyl)-semicarbazide
    VPC23019
    (R)-phosphoric acid mono-[2-amino-2-(3-octyl-phenylcarbamoyl)-ethyl] ester
    SD
    Sprague-Dawley
    IkAch
    cardiac G protein-gated potassium channel
    Eu-GTP
    europium-GTP
    LC/MS/MS
    liquid chromatography/tandem mass spectrometry
    U46619
    9,11-dideoxy-9α,11α-methanoepoxy prostaglandin F2α
    FTY-720
    fingolimod
    Y-27632
    (R)-(+)-trans-4-(1-aminoethyl)-N-(4-pyridyl)cyclohexanecarboxamide dihydrochloride monohydrate
    SEW2871
    5-[4-phenyl-5-(trifluoromethyl)-2-thienyl]-3-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole.

    • Received October 13, 2009.
    • Accepted January 19, 2010.
  • Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 77 (4)
Molecular Pharmacology
Vol. 77, Issue 4
1 Apr 2010
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Research ArticleArticle

Sphingosine 1-Phosphate (S1P) Regulates Vascular Contraction via S1P3 Receptor: Investigation Based on a New S1P3 Receptor Antagonist

Akira Murakami, Hiroshi Takasugi, Shinya Ohnuma, Yuuki Koide, Atsuko Sakurai, Satoshi Takeda, Takeshi Hasegawa, Jun Sasamori, Takashi Konno, Kenji Hayashi, Yoshiaki Watanabe, Koji Mori, Yoshimichi Sato, Atsuo Takahashi, Naoki Mochizuki and Nobuyuki Takakura
Molecular Pharmacology April 1, 2010, 77 (4) 704-713; DOI: https://doi.org/10.1124/mol.109.061481

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Research ArticleArticle

Sphingosine 1-Phosphate (S1P) Regulates Vascular Contraction via S1P3 Receptor: Investigation Based on a New S1P3 Receptor Antagonist

Akira Murakami, Hiroshi Takasugi, Shinya Ohnuma, Yuuki Koide, Atsuko Sakurai, Satoshi Takeda, Takeshi Hasegawa, Jun Sasamori, Takashi Konno, Kenji Hayashi, Yoshiaki Watanabe, Koji Mori, Yoshimichi Sato, Atsuo Takahashi, Naoki Mochizuki and Nobuyuki Takakura
Molecular Pharmacology April 1, 2010, 77 (4) 704-713; DOI: https://doi.org/10.1124/mol.109.061481
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