Prostaglandin E₂ Inhibits Proteinase-Activated Receptor 2-Signal Transduction through Regulation of Receptor Internalization
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- KOMATSU Hiroyuki
- Laboratory of Veterinary Pharmacology, Joint Faculty of Veterinary Medicine, Yamaguchi University, 1677–1 Yoshida, Yamaguchi 753–8515, Japan
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- ENJOUJI Shuhei
- Laboratory of Veterinary Pharmacology, Joint Faculty of Veterinary Medicine, Yamaguchi University, 1677–1 Yoshida, Yamaguchi 753–8515, Japan
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- ITO Akihiro
- Laboratory of Veterinary Pharmacology, Joint Faculty of Veterinary Medicine, Yamaguchi University, 1677–1 Yoshida, Yamaguchi 753–8515, Japan
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- OHAMA Takashi
- Laboratory of Veterinary Pharmacology, Joint Faculty of Veterinary Medicine, Yamaguchi University, 1677–1 Yoshida, Yamaguchi 753–8515, Japan
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- SATO Koichi
- Laboratory of Veterinary Pharmacology, Joint Faculty of Veterinary Medicine, Yamaguchi University, 1677–1 Yoshida, Yamaguchi 753–8515, Japan
書誌事項
- タイトル別名
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- Prostaglandin E<sub>2</sub> Inhibits Proteinase-Activated Receptor 2-Signal Transduction through Regulation of Receptor Internalization
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抄録
Proteinase-activated receptor (PAR) is expressed on various cells, and the PAR family consists of PAR1, PAR2, PAR3, and PAR4. Individual PARs are activated during inflammatory conditions in which they regulate inflammatory responses in various diseases. For example, PAR activation is known to induce prostaglandin E2 (PGE2) production, and then upregulated PGE2 suppresses PAR1 expression in a negative feedback loop. Surprisingly, PGE2 effects on PAR2, which is a well-researched and attractive target for drug development, remain unknown. Therefore, we investigated PAR2 regulation by PGE2. Using HEK293T cells, we showed that PGE2 inhibits extracellular signal-regulated kinase (ERK) phosphorylation induced by a PAR2-activating peptide (PAR2-AP). AH-6809 (an inhibitor of PGE2 receptors 1 [EP1] and 2 [EP2]), but not ONO-AE3-208 (a PGE2 receptor 4 [EP4] inhibitor), reversed the inhibitory effects of PGE2 on PAR2-AP-induced ERK phosphorylation. Studies on PAR2 expression revealed that PGE2 suppressed cell surface expression of PAR2 and induced internalization of PAR2, and not PAR4, in N2a mouse neuroblastoma cells that were transiently transfected with either PAR2 or PAR4. Furthermore, forskolin, an adenylate cyclase activator, induced PAR2 internalization and inhibited PAR2-AP-induced phosphorylation of ERK. Because EP2 (not EP1) also increases intracellular cyclic AMP, we conclude that PGE2 inhibited PAR2-dependent signal transduction by inducing the internalization of PAR2 through an EP2-dependent increase in intracellular cyclic AMP. This novel regulatory pathway in which PAR2 function is regulated by PGE2 will broaden our understanding of PAR2-dependent inflammation and could provide novel strategies for drug development.
収録刊行物
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- The Journal of Veterinary Medical Science
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The Journal of Veterinary Medical Science 75 (3), 255-261, 2013
公益社団法人 日本獣医学会
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詳細情報 詳細情報について
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- CRID
- 1390282681405594240
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- NII論文ID
- 130001879641
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- NII書誌ID
- AA10796138
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- COI
- 1:STN:280:DC%2BC3s%2FltVektQ%3D%3D
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- ISSN
- 13477439
- 09167250
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- NDL書誌ID
- 024430551
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- PubMed
- 23064451
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- 本文言語コード
- en
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- データソース種別
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- JaLC
- NDL
- Crossref
- PubMed
- CiNii Articles
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- 抄録ライセンスフラグ
- 使用不可