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Originally published In Press as doi:10.1074/jbc.M208051200 on September 19, 2002

J. Biol. Chem., Vol. 277, Issue 47, 44898-44904, November 22, 2002
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Requirement of Phosphatidylinositol 3-Kinase Activation and Calcium Influx for Leukotriene B4-induced Enzyme Release*

Nobuko ItoDagger §, Takehiko YokomizoDagger ||**Dagger Dagger , Takehiko Sasaki**§§, Hiroshi Kurosu¶¶, Josef Penninger||||, Yasunori Kanaho§§, Toshiaki Katada¶¶, Kazuo Hanaoka§, and Takao ShimizuDagger ||

From the Dagger  Department of Biochemistry and Molecular Biology, § Department of Anesthesiology, Faculty of Medicine, and ¶¶ Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, and || CREST and ** PRESTO of Japan Science and Technology Corp., Tokyo 113-0033, Japan, the §§ Department of Pharmacology, the Tokyo Metropolitan Institute of Medical Science, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo 113-8613, Japan, and |||| Institute for Molecular Biotechnology of the Austrian Academy of Sciences, c/o Dr. Bohr Gasse, A-1030 Vienna, Austria

Leukotriene B4 (LTB4) is a potent lipid mediator involved in host defense and inflammatory responses. It causes chemotaxis, generation of reactive oxygen species, and degranulation. However, only little is known of the molecular mechanisms by which LTB4 induces these biological activities. To analyze the intracellular signaling pathways to mediate lysosomal enzyme release through the cloned LTB4 receptor (BLT1), we transfected BLT1 to rat basophilic leukemia cells (RBL-2H3). LTB4 dose-dependently released beta -hexosaminidase, and the release was mostly inhibited when the cells were pretreated with pertussis toxin, indicating that the degranulation is mediated by Gi proteins. LTB4 activated phosphatidylinositol 3-kinase (PI3-K) through Gi, and inhibition of PI3-K by wortmannin or LY290042 inhibited degranulation. Granulocytes from PI3-Kgamma -deficient mice showed reduced LTB4-induced degranulation, suggesting that this isozyme of PI3-K is involved in the degranulation. LTB4 also caused calcium release from intracellular stores and calcium influx from the outside milieu through Gi, but only the calcium influx is critical for the lysosomal enzyme release. Calcium influx and PI3-K activation are both downstream events of Gi, since they were inhibited by pertussis toxin. These two events are in essence independent each other, because calcium depletion did not affect PI3-K, and inhibition of PI3-K did not attenuate calcium influx significantly. Thus, our results have clearly shown that LTB4 binds BLT1 and activates Gi-like protein, and both PI3-Kgamma activation and a sustained calcium elevation by calcium influx are necessary for enzyme release in these cells.

* This work was supported in part by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology and the Japan Society for the Promotion of Science.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Present address: Neural Plasticity Research Group, Dept. of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129.

Dagger Dagger Recipient of grants from the Yamanouchi Foundation for Metabolic Disorders and the Uehara Memorial Foundation. To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, Faculty of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan. Tel.: 81-3-5802-2925; Fax: 81-3-3813-8732; E-mail: yokomizo-tky@umin.ac.jp.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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