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Originally published In Press as doi:10.1074/jbc.M110210200 on April 4, 2002

J. Biol. Chem., Vol. 277, Issue 25, 22685-22691, June 21, 2002
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Distinct Roles of Receptor Phosphorylation, G Protein Usage, and Mitogen-activated Protein Kinase Activation on Platelet Activating Factor-induced Leukotriene C4 Generation and Chemokine Production*

Jasimuddin Ahamed and Hydar AliDagger

From the Department of Pathology, University of Pennsylvania School of Dental Medicine, Philadelphia, Pennsylvania 19104

Platelet activating factor (PAF) interacts with cell surface G protein-coupled receptors on leukocytes to induce degranulation, leukotriene C4 (LTC4) generation, and chemokine CCL2 production. Using a basophilic leukemia RBL-2H3 cell line expressing wild-type PAF receptor (PAFR) and a phosphorylation-deficient mutant (mPAFR), we have previously demonstrated that receptor phosphorylation mediates desensitization of PAF-induced degranulation. Here, we sought to determine the role of receptor phosphorylation on PAF-induced LTC4 generation and CCL2 production. We found that PAF caused a significantly enhanced LTC4 generation in cells expressing mPAFR when compared with PAFR cells. In contrast, PAF-induced CCL2 production was greatly reduced in mPAFR cells. Pertussis toxin and U0126, which inhibit Gi and p44/42 mitogen-activated protein kinase (ERK) activation, respectively, caused very little inhibition of PAF-induced CCL2 production (~20% inhibition). In contrast, these inhibitors almost completely blocked both PAF-induced ERK phosphorylation and LTC4 generation in PAFR cells. However, in mPAFR cells pertussis toxin only partially inhibited PAF-induced ERK phosphorylation. A Ca2+/calmodulin inhibitor had no effect on PAF-induced ERK phosphorylation in PAFR cells but completely blocked the response in mPAFR cells. These data demonstrate that receptor phosphorylation, which serves to desensitize PAF-induced LTC4 generation, is required for chemokine CCL2 production. They also indicate a previously unrecognized selectivity in G protein usage and ERK activation for PAF-induced responses. Whereas PAF-induced CCL2 production is, in large part, mediated independently of Gi activation or ERK phosphorylation, LTC4 generation requires ERK phosphorylation, which is mediated by different G proteins depending on the phosphorylation status of the receptor.

* This work was supported by National Institutes of Health Grants HL-54166 and HL-63372.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.

Dagger To whom correspondence should be addressed: Dept. of Pathology, University of Pennsylvania School of Dental Medicine, 4010 Locust St. (346 Levy Bldg.), Philadelphia, PA 19104-6002. Tel.: 215-573-1993; Fax: 215-573-2050; E-mail: ali@path.dental.upenn.edu.

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