Prostaglandin EP3 receptor superactivates adenylyl cyclase via the Gq/PLC/Ca pathway in a lipid raft-dependent manner |
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Authors: | Kumiko Yamaoka Kenji Kuroiwa Tomoaki Inazumi Hiroyuki Tabata Satoshi Tanaka Atsushi Ichikawa Yukihiko Sugimoto |
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Affiliation: | a Department of Physiological Chemistry, Kyoto University Graduate School of Pharmaceutical Sciences, Sakyo-ku, Kyoto 606-8501, Japan b Department of Systems Bioscience for Drug Discovery, Kyoto University Graduate School of Pharmaceutical Sciences, Sakyo-ku, Kyoto 606-8501, Japan c School of Pharmacy and Pharmaceutical Sciences, Mukogawa Women’s University, Koshien, Nishinomiya, Hyogo 663-8179, Japan d Department of Pharmaceutical Biochemistry, Kumamoto University Graduate School of Medical and Pharmaceutical Sciences, Kumamoto 862-0973, Japan |
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Abstract: | We previously demonstrated that prostaglandin EP3 receptor augments EP2-elicited cAMP formation in COS-7 cells in a Gi/o-insensitive manner. The purpose of our current study was to identify the signaling pathways involved in EP3-induced augmentation of receptor-stimulated cAMP formation. The enhancing effect of EP3 receptor was irrespective of the C-terminal structure of the EP3 isoform. This EP3 action was abolished by treatment with inhibitors for phospholipase C and intracellular Ca2+-related signaling molecules such as U73122, staurosporine, 2-APB and SK&F 96365. Indeed, an EP3 agonist stimulated IP3 formation and intracellular Ca2+ mobilization, which was blocked by U73122, but not by pertussis toxin. The enhancing effect by EP3 on cAMP formation was mimicked by both a Ca2+ ionophore and the activation of a typical Gq-coupled receptor. Moreover, EP3 was exclusively localized to the raft fraction in COS-7 cells and EP3-elicited augmentation of cAMP formation was abolished by cholesterol depletion and introduction of a dominant negative caveolin-1 mutant. These results suggest that EP3 elicits adenylyl cyclase superactivation via Gq/phospholipase C activation and intracellular Ca2+ mobilization in a lipid raft microdomain-dependent manner. |
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Keywords: | Raft Caveolin Signal cross-talk Prostanoid GPCR |
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