Abstract
We recently demonstrated that endothelin-1 (ET-1) activates two types of Ca(2+)-permeable nonselective cation channel (designated NSCC-1 and NSCC-2) in Chinese hamster ovarian cells expressing endothelin(B) receptor (CHO-ET(B)R). These channels can be discriminated using the Ca(2+) channel blockers, LOE 908 and SK&F 96365. LOE 908 is a blocker of NSCC-1 and NSCC-2, whereas SK&F 96365 is a blocker of NSCC-2. In this study, we investigated the possible role of phosphoinositide 3-kinase (PI3K) in the ET-1-induced activation of NSCCs in CHO-ET(B)R using wortmannin and LY-294002, inhibitors of PI3K. ET-1-induced Ca(2+) influx was partially inhibited in CHO-ET(B)R pretreated with wortmannin or LY-294002. In contrast, addition of wortmannin or LY-294002 after stimulation with ET-1 did not suppress Ca(2+) influx. The Ca(2+) channels activated by ET-1 in wortmannin- or LY-294002-treated CHO-ET(B)R were sensitive to LOE 908 and resistant to SK&F 96365. In conclusion, NSCC-2 is stimulated by ET-1 via PI3K-dependent cascade, whereas NSCC-1 is stimulated independently of the PI3K pathway. Moreover, PI3K seems to be required for the initiation of the Ca(2+) entry through NSCC-2 but not for its maintenance.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetamides / pharmacology
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Androstadienes / pharmacology
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Animals
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CHO Cells
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Calcium / metabolism
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Calcium Channel Blockers / pharmacology
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Calcium Signaling / drug effects
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Calcium Signaling / physiology
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Cell Membrane / drug effects
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Cell Membrane / enzymology*
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Chromones / pharmacology
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Cricetinae
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Endothelin-1 / metabolism*
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Endothelin-1 / pharmacology
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Endothelium, Vascular / enzymology*
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Enzyme Inhibitors / pharmacology
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Imidazoles / pharmacology
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Ion Channels / drug effects
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Ion Channels / metabolism*
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Isoquinolines / pharmacology
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Morpholines / pharmacology
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Phosphatidylinositol 3-Kinases / metabolism*
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Receptor, Endothelin B
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Receptors, Endothelin / drug effects
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Receptors, Endothelin / genetics
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Receptors, Endothelin / metabolism*
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Signal Transduction / drug effects
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Signal Transduction / physiology
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Up-Regulation / drug effects
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Up-Regulation / physiology
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Wortmannin
Substances
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Acetamides
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Androstadienes
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Calcium Channel Blockers
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Chromones
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Endothelin-1
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Enzyme Inhibitors
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Imidazoles
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Ion Channels
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Isoquinolines
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Morpholines
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Receptor, Endothelin B
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Receptors, Endothelin
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LOE 908
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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Phosphatidylinositol 3-Kinases
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1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole
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Calcium
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Wortmannin