Different Pathways for Activation of Extracellular Signal-Regulated Kinase through Thromboxane A_2 Receptor Isoforms(Pharmacology)

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Thromboxane A_2 receptor (TP) consists of two alternatively spliced isoforms, TPα and TPβ, which differ in their cytoplasmic tails. In the present study, we examined the difference in signal transduction of TPα and TPβ, using stably expressing cells of TPα and TPβ. The cells expressing TPα (TPα-SC2) and TPβ (TPβ-SC15) were selected based on the similar binding sites of [^3H]-SQ29548, a TP antagonist. U46619, a TP agonist, elicited phosphoinositide hydrolysis in TPα-SC2 and TPβ-SC15 cells with a similar concentration-dependency. U46619 also caused the phosphorylation of extracellular signal-regulated kinase (ERK1/2) in both TPα-SC2 and TPβ-SC15 cells. While the peak of the phosphorylation of ERK1/2 was observed 5 min after addition of U46619 in TPα-SC2 cells, the long lasting phosphorylation up to 60 min was in TPβ-SC15 cells. U46619-induced phosphorylation of ERK1/2 at 5 min was inhibited by pertussis toxin in both cells, suggesting that G_i is involved in the phosphorylation mediated via both TP isoforms. Interfering G_<12/13> activity by overexpression of p115-RGS reduced U46619-induced ERK1/2 phosphorylation in TPβ-SC15 cells, but not in TPα-SC2 cells. H89, an inhibitor of protein kinase A (PKA), reduced U46619-induced ERK1/2 phosphorylation in TPα-SC2 cells, but not in TPβ-SC15 cells. These results indicate that G_i may be involved in TP-mediated ERK1/2 phosphorylation in both isoforms. In addition, H89-sensitive kinase and G_<12/13> may be involved in TP-mediated ERK1/2 phosphorylation in TPα and TPβ, respectively.
公益社団法人日本薬学会の論文
2006-04-01

Different Pathways for Activation of Extracellular Signal-Regulated Kinase through Thromboxane A_2 Receptor Isoforms(Pharmacology)

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