Differential Coupling of Human Endothelin Type A Receptor to Gq/11 and G12 Proteins: the Functional Significance of Receptor Expression Level in Generating Multiple Receptor Signaling
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- Horinouchi Takahiro
- Department of Cellular Pharmacology, Hokkaido University Graduate School of Medicine, Japan
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- Asano Hiroshi
- Department of Cellular Pharmacology, Hokkaido University Graduate School of Medicine, Japan
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- Higa Tunaki
- Department of Cellular Pharmacology, Hokkaido University Graduate School of Medicine, Japan
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- Nishimoto Arata
- Department of Cellular Pharmacology, Hokkaido University Graduate School of Medicine, Japan
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- Nishiya Tadashi
- Department of Cellular Pharmacology, Hokkaido University Graduate School of Medicine, Japan
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- Muramatsu Ikunobu
- Division of Pharmacology, Department of Biochemistry and Bioinformative Sciences, School of Medicine, University of Fukui, Japan
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- Miwa Soichi
- Department of Cellular Pharmacology, Hokkaido University Graduate School of Medicine, Japan
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This study examines the influence of receptor expression level on signaling pathways activated via endothelin type A receptor (ETAR) expressed in Chinese hamster ovary cells at 32,100 (ETAR-high-CHO) and 893 (ETAR-low-CHO) fmolmg protein−1. Endothelin-1 (ET-1) elicited a sustained increase in intracellular Ca2+ concentration ([Ca2+]i), which was dependent on Gq/11 protein, phospholipase C (PLC), Na+/H+ exchanger (NHE), and p38 mitogen–activated protein kinase (p38MAPK) in ETAR-high-CHO, whereas the sustained [Ca2+]i increase was negligible in ETAR-low-CHO. Functional study with CytosensorTM microphysiometer showed that ET-1 evoked an NHE1-mediated increase in extracellular acidification rate (ECAR) in ETAR-high-CHO and ETAR-low-CHO. In ETAR-high-CHO, the ECAR response at 30 min after ET-1 stimulation was insensitive to Gq/11 and PLC inhibitors, but sensitive to the p38MAPK inhibitor. In ETAR-low-CHO, the ECAR response at 30 min was sensitive to these inhibitors. Western blot analysis demonstrated that ET-1–induced p38MAPK phosphorylation in ETAR-low-CHO but not in ETAR-high-CHO was mediated via Gq/11 and PLC. The Gq/11/PLC-independent p38MAPK phosphorylation in ETAR-high-CHO was suppressed by expression of the C terminus of Gα12 protein to disrupt receptor-G12 protein coupling. These results provide evidence for multiple signaling pathways of ETAR that were activated via at least the Gq/11/PLC/NHE, G12/p38MAPK/NHE, and Gq/11/PLC/p38MAPK/NHE cascades in an expression level–dependent manner.<br>
収録刊行物
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- Journal of Pharmacological Sciences
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Journal of Pharmacological Sciences 111 (4), 338-351, 2009
公益社団法人 日本薬理学会
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詳細情報 詳細情報について
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- CRID
- 1390001205179782272
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- NII論文ID
- 10026154456
- 130000132483
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- NII書誌ID
- AA11806667
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- COI
- 1:CAS:528:DC%2BC3cXhs1Oktw%3D%3D
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- ISSN
- 13478648
- 13478613
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- NDL書誌ID
- 10492452
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- PubMed
- 19942800
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- 本文言語コード
- en
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- データソース種別
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- JaLC
- NDL
- Crossref
- PubMed
- CiNii Articles
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- 使用不可