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Pertussis Toxin Up-regulates Angiotensin Type 1 Receptors through Toll-like Receptor 4-mediated Rac Activation*

By Motohiro Nishida, Reiko Suda, Yuichi Nagamatsu, Shihori Tanabe, Naoya Onohara, Michio Nakaya, Yasunori Kanaho, Takahiro Shibata, Koji Uchida, Hideki Sumimoto, Yoji Sato and Hitoshi Kurose


Pertussis toxin (PTX) is recognized as a specific tool that uncouples receptors from Gi and Go through ADP-ribosylation. During the study analyzing the effects of PTX on Ang II type 1 receptor (AT1R) function in cardiac fibroblasts, we found that PTX increases the number of AT1Rs and enhances AT1R-mediated response. Microarray analysis revealed that PTX increases the induction of interleukin (IL)-1β among cytokines. Inhibition of IL-1β suppressed the enhancement of AT1R-mediated response by PTX. PTX increased the expression of IL-1β and AT1R through NF-κB, and a small GTP-binding protein, Rac, mediated PTX-induced NF-κB activation through NADPH oxidase-dependent production of reactive oxygen species. PTX induced biphasic increases in Rac activity, and the Rac activation in a late but not an early phase was suppressed by IL-1β siRNA, suggesting that IL-1β-induced Rac activation contributes to the amplification of Rac-dependent signaling induced by PTX. Furthermore, inhibition of TLR4 (Toll-like receptor 4) abolished PTX-induced Rac activation and enhancement of AT1R function. However, ADP-ribosylation of Gi/Go by PTX was not affected by inhibition of TLR4. Thus, PTX binds to two receptors; one is TLR4, which activates Rac, and another is the binding site that is required for ADP-ribosylation of Gi/Go

Topics: Signal Transduction
Publisher: American Society for Biochemistry and Molecular Biology
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Provided by: PubMed Central
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