G12/13 and Gq mediate S1P2-induced inhibition of Rac and migration in vascular smooth muscle in a manner dependent on Rho but not Rho kinase

フォーマット:

論文

責任表示:

Takashima, Shinichiro ; Sugimoto, Naotoshi ; Takuwa, Noriko ; Okamoto, Yasuo ; Yoshioka, Kazuaki ; Takamura, Masayuki ; Takata, Shigeo ; Kaneko, Shuichi ; Takuwa, Yoh

言語:

英語

出版情報:

Elsevier, 2008-09-01

著者名:

Takashima, Shinichiro

Sugimoto, Naotoshi

Takuwa, Noriko

Okamoto, Yasuo

Yoshioka, Kazuaki

Takamura, Masayuki

Takata, Shigeo

Kaneko, Shuichi

Takuwa, Yoh

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掲載情報:

Cardiovascular Research

ISSN:

0008-6363      

巻:

79

通号:

4

開始ページ:

689

終了ページ:

697

バージョン:

author

概要:

金沢大学医薬保健研究域医学系<br />Aims: The lysophospholipid mediator sphingosine-1-phosphate (S1P) activates G protein-coupled receptors (GPCRs) to induce potent inhibition of platelet-derived growth factor (PDGF)-induced Rac activation and, there … by, chemotaxis in rat vascular smooth muscle cells (VSMCs). We explored the heterotrimeric G protein and the downstream mechanism that mediated S1P inhibition of Rac and cell migration in VSMCs. Methods and results: S1P inhibition of PDGF-induced cell migration and Rac activation in VSMCs was abolished by the selective S1P2 receptor antagonist JTE-013. The C-terminal peptides of Gα subunits (Gα-CTs) act as specific inhibitors of respective G protein-GPCR coupling. Adenovirus-mediated expression of Gα12-CT, Gα13-CT, and Gα q-CT, but not that of Gαs-CT or LacZ or pertussis toxin treatment, abrogated S1P inhibition of PDGF-induced Rac activation and migration, indicating that both G12/13 and Gq classes are necessary for the S1P inhibition. The expression of Gαq-CT as well as Gα12-CT and Gα13-CT also abolished S1P-induced Rho stimulation. C3 toxin, but not a Rho kinase inhibitor or a dominant negative form of Rho kinase, abolished S1P inhibition of PDGF-induced Rac activation and cell migration. The angiotensin II receptor AT1, which robustly couples to Gq, did not mediate either Rho activation or inhibition of PDGF-induced Rac activation or migration, suggesting that activation of Gq alone was not sufficient for Rho activation and resultant Rac inhibition. However, the AT1 receptor fused to Gα12 was able to induce not only Rho stimulation but also inhibition of PDGF-induced Rac activation and migration. Phospholipase C inhibition did not affect S1P-induced Rho activation, and protein kinase C activation by a phorbol ester did not mimic S1P action, suggesting that S1P inhibition of migration or Rac was not dependent on the phospholipase C pathway. Conclusion: These observations together suggest that S1P2 mediates inhibition of Rac and migration through the coordinated action of G 12/13 and Gq for Rho activation in VSMCs. © The Author 2008.. 続きを見る

URL:

http://hdl.handle.net/2297/12043