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Attenuation of ligand-induced activation of angiotensin II type 1 receptor signaling by the type 2 receptor via protein kinase C

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Title: Attenuation of ligand-induced activation of angiotensin II type 1 receptor signaling by the type 2 receptor via protein kinase C
Authors: Inuzuka, Takayuki Browse this author
Fujioka, Yoichiro Browse this author
Tsuda, Masumi Browse this author →KAKEN DB
Fujioka, Mari Browse this author
Satoh, Aya O. Browse this author
Horiuchi, Kosui Browse this author
Nishide, Shinya Browse this author →KAKEN DB
Nanbo, Asuka Browse this author →KAKEN DB
Tanaka, Shinya Browse this author →KAKEN DB
Ohba, Yusuke Browse this author →KAKEN DB
Issue Date: 9-Feb-2016
Publisher: Nature Publishing Group
Journal Title: Scientific reports
Volume: 6
Start Page: 21613
Publisher DOI: 10.1038/srep21613
Abstract: Angiotensin II (AII) type 2 receptor (AT2R) negatively regulates type 1 receptor (AT1R) signaling. However, the precise molecular mechanism of AT2R-mediated AT1R inhibition remains poorly understood. Here, we characterized the local and functional interaction of AT2R with AT1R. AT2R colocalized and formed a complex with AT1R at the plasma membrane, even in the absence of AII. Upon AII stimulation, the spatial arrangement of the complex was modulated, as confirmed by Forster resonance energy transfer (FRET) analysis, followed by AT2R internalization along with AT1R. AT2R internalization was specifically observed only in the presence of AT1R; AT2R alone could not be internalized. The AT1R-specific inhibitor losartan completely inhibited both the conformational change and the internalization of AT2R with AT1R, whereas the AT2R-specific inhibitor PD123319 partially hindered these phenomena, demonstrating that the activation of both receptors was indispensable for these effects. In addition, treatment with the protein kinase C (PKC) inhibitors inhibited the ligand-dependent accumulation of AT2R but not that of AT1R in the endosomes. A mutation in the putative phosphorylation sites of AT2R also abrogated the co-internalization of ATR2 with AT1R and the inhibitory effect of ATR2 on AT1R. These data suggest that AT2R inhibits ligand-induced AT1R signaling through the PKC-dependent pathway.
Type: article
Appears in Collections:医学院・医学研究院 (Graduate School of Medicine / Faculty of Medicine) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 大場 雄介

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