Leukotriene-induced hydrolysis of inositol lipids in guinea pig lung: mechanism of signal transduction for leukotriene-D4 receptors.
Addition of leukotriene D4 (LTD4) to [3H]myo-inositol-labeled guinea pig lung induced rapid breakdown of inositol lipids. Formation of [3H]inositol trisphosphate was rapid, with a peak of 140-160% of the control level, 30 sec post-treatment. Formation of [3H]inositol bisphosphate and [3H]inositol monophosphate ([3H]IP1) was also rapid in the presence of LiCl. LTD4-induced [3H]IP1 formation was concentration dependent, stereoselective, and not inhibited by the cyclooxygenase inhibitor, indomethacin. Agonist analogs of LTD4 and leukotriene E4 also induced dose-dependent increases in the synthesis of [3H]IP1. The rank order potency of the agonist-induced [3H]IP1 formation was equivalent to those reported for LTD4 receptor binding, smooth muscle contraction, and thromboxane B2 biosynthesis. Furthermore, a specific receptor antagonist, SKF 102922, inhibited LTD4-induced [3H]IP1 formation in guinea pig lung. These studies suggest that LTD4 may interact with membrane receptor and activate a phospholipase C, which in turn induces the hydrolysis of inositol lipids. The hydrolysis products, diacylglycerol and inositol trisphosphate, can be regarded as the intracellular messengers for LTD4 receptors in guinea pig lung. This concept may explain a variety of pharmacological effects of leukotrienes in different types of target cells or tissues.
D000818:Animals; D003998:Dicarboxylic Acids / Q000494:pharmacology; D006168:Guinea Pigs; D007213:Indomethacin / Q000494:pharmacology; D007295:Inositol Phosphates / Q000378:metabolism*; D017999:Leukotriene E4; D008168:Lung / Q000378:metabolism*; D009130:Muscle, Smooth / Q000502:physiology; D010716:Phosphatidylinositols / Q000378:metabolism*; D018077:Receptors, Leukotriene; D011982:Receptors, Prostaglandin / Q000187:drug effects / Q000502:physiology*; D013189:SRS-A / Q000031:analogs & derivatives / Q000494:pharmacology*; D013403:Sugar Phosphates / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013929:Thromboxane B2 / Q000378:metabolism
D003998:Dicarboxylic Acids; D007295:Inositol Phosphates; D010716:Phosphatidylinositols; D018077:Receptors, Leukotriene; D011982:Receptors, Prostaglandin; D013189:SRS-A; D013403:Sugar Phosphates; D013929:Thromboxane B2; D017999:Leukotriene E4; C046472:5-(2-(8-phenyloctyl)phenyl)-4,6-dithianonanedioic acid; D013755:Tetradecanoylphorbol Acetate; D007213:Indomethacin