Sphingosine 1-Phosphate (S1P) Regulates Vascular Contraction via S1P3 Receptor: Investigation Based on a New S1P3 Receptor Antagonist
| Autor: | Naoki Mochizuki, Yuuki Koide, Yoshimichi Sato, Atsuko Sakurai, Shinya Ohnuma, Atsuo Takahashi, Satoshi Takeda, Takeshi Hasegawa, Jun Sasamori, Yoshiaki Watanabe, Akira Murakami, Nobuyuki Takakura, Takashi Konno, Koji Mori, Hiroshi Takasugi, Kenji Hayashi |
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| Rok vydání: | 2010 |
| Předmět: |
Male
Agonist medicine.medical_specialty Vascular smooth muscle medicine.drug_class CHO Cells Biology Calcium in biology Rats Sprague-Dawley chemistry.chemical_compound Cricetulus Dogs Heart Rate Sphingosine Coronary Circulation Cricetinae Internal medicine medicine Animals Sphingosine-1-phosphate Phosphorylation Extracellular Signal-Regulated MAP Kinases Receptor Pharmacology rho-Associated Kinases Fingolimod Hydrochloride organic chemicals Hydrazones Antagonist Cerebral Arteries Receptor antagonist Molecular biology Rats Receptors Lysosphingolipid Endocrinology chemistry Propylene Glycols Vasoconstriction Molecular Medicine Calcium lipids (amino acids peptides and proteins) Lysophospholipids |
| Zdroj: | Molecular Pharmacology. 77:704-713 |
| ISSN: | 1521-0111 0026-895X |
| DOI: | 10.1124/mol.109.061481 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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