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

被引：30

作者：

Tolloczko, B ^{[1
]}

Turkewitsch, P ^{[1
]}

Al-Chalabi, M ^{[1
]}

Martin, JG ^{[1
]}

机构：

[1] McGill Univ, Meakins Christie Labs, Montreal, PQ H2 2P2, Canada

来源：

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS | 2004年 / 311卷 / 02期

关键词：

D O I：

10.1124/jpet.104.069013

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

Phosphoinositide 3-kinase (PI3K) may potentially influence intracellular [Ca2+](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 Ca2+ signaling in rat airway smooth muscle (ASM) cells using fura-2 and imaging methodology. Wortmannin ( 1 muM) and LY-294002 ( 1 and 10 muM) had opposite effects: wortmannin caused a small increase, whereas LY-294002 caused a significant decrease of peak Ca2+ responses to serotonin (5-HT). LY-294002 ( 10 muM) 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 muM) reduced 5-HT-triggered responses to a similar extent as LY-294002. We conclude that LY-294002 modulates Ca2+ signaling in rat ASM independently of its action on PI3K by acting on, or upstream of, PLC, possibly by inhibiting CK2.

引用

页码：787 / 793

页数：7

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