LY-294002 [2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one] affects calcium signaling in airway smooth muscle cells independently of phosphoinositide 3-kinase inhibition
| Autor: | Mustafa Al-Chalabi, Barbara Tolloczko, James G. Martin, Petra Turkewitsch |
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| Rok vydání: | 2004 |
| Předmět: |
Male
medicine.medical_specialty Serotonin Morpholines Myocytes Smooth Muscle Bronchi Biology Wortmannin chemistry.chemical_compound Internal medicine medicine Myocyte Animals Drug Interactions Phosphatidylinositol Calcium Signaling Enzyme Inhibitors Calcium signaling Phosphoinositide-3 Kinase Inhibitors Pharmacology Calcium metabolism Phosphoinositide 3-kinase Phospholipase C Molecular biology Rats Inbred F344 Rats Androstadienes Enzyme Activation Endocrinology chemistry Chromones biology.protein Molecular Medicine Calcium Intracellular Dichlororibofuranosylbenzimidazole Muscle Contraction |
| Zdroj: | The Journal of pharmacology and experimental therapeutics. 311(2) |
| ISSN: | 0022-3565 |
| Popis: | Phosphoinositide 3-kinase (PI3K) may potentially influence intracellular [Ca(2+)](i) concentration by several mechanisms. We have investigated the effects of phosphoinositide 3-kinase (PI3K) inhibitors wortmannin and LY-294002 [2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one] on Ca(2+) signaling in rat airway smooth muscle (ASM) cells using fura-2 and imaging methodology. Wortmannin (1 microM) and LY-294002 (1 and 10 microM) had opposite effects: wortmannin caused a small increase, whereas LY-294002 caused a significant decrease of peak Ca(2+) responses to serotonin (5-HT). LY-294002 (10 microM) diminished 5-HT-induced ASM cell contraction, measured as a change in cell surface area, and inositol phosphate formation, measured by anion exchange chromatography. Thin layer chromatography revealed that the levels of phospholipase C (PLC) substrate phosphatidylinositol 4,5-bisphosphate were not affected. SDS polyacrylamide gel electrophoresis and Western blotting have shown that both wortmannin and LY-294002 inhibited platelet-derived growth factor-induced PI3K activation. However, PI3K activation could not be detected after 5-HT stimulation. The specific casein kinase-2 (CK2) inhibitor 5,6-dichloro-1-beta-d-ribofuranosyl-benzimidazole (10-40 microM) reduced 5-HT-triggered responses to a similar extent as LY-294002. We conclude that LY-294002 modulates Ca(2+) signaling in rat ASM independently of its action on PI3K by acting on, or upstream of, PLC, possibly by inhibiting CK2. |
| Databáze: | OpenAIRE |
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