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Originally published In Press as doi:10.1074/jbc.M211787200 on January 14, 2003

J. Biol. Chem., Vol. 278, Issue 14, 11874-11878, April 4, 2003
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Distinct Phosphoinositide 3-Kinases Mediate Mast Cell Degranulation in Response to G-protein-coupled Versus Fcepsilon RI Receptors*

David A. WindmillerDagger and Jonathan M. Backer§

From the Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461

Phosphoinositide (PI) 3-kinases are critical regulators of mast cell degranulation. The Class IA PI 3-kinases p85/p110beta and p85/p110delta but not p85/p110alpha are required for antigen-mediated calcium flux in RBL-2H3 cells (Smith, A. J., Surviladze, Z., Gaudet, E. A., Backer, J. M., Mitchell, C. A., and Wilson, B. S. et al., (2001) J. Biol. Chem. 276, 17213-17220). We now examine the role of Class IA PI 3-kinases isoforms in degranulation itself, using a single-cell degranulation assay that measures the binding of fluorescently tagged annexin V to phosphatidylserine in the outer leaflet of the plasma membrane of degranulated mast cells. Consistent with previous data, antibodies against p110delta and p110beta blocked Fcepsilon R1-mediated degranulation in response to Fcepsilon RI ligation. However, antigen-stimulated degranulation was also inhibited by antibodies against p110alpha , despite the fact that these antibodies have no effect on antigen-induced calcium flux. These data suggest that p110alpha mediates a calcium-independent signal during degranulation. In contrast, only p110beta was required for enhancement of antigen-stimulated degranulation by adenosine, which augments mast cell-mediated airway inflammation in asthma. Finally, we examined carbachol-stimulated degranulation in RBL2H3 cells stably expressing the M1 muscarinic receptor (RBL-2H3-M1 cells). Surprisingly, carbachol-stimulated degranulation was blocked by antibody-mediated inhibition of the Class III PI 3-kinase hVPS34 or by titration of its product with FYVE domains. Antibodies against Class IA PI 3-kinases had no effect. These data demonstrate: (a) a calcium-independent role for p110alpha in antigen-stimulated degranulation; (b) a requirement for p110beta in adenosine receptor signaling; and (c) a requirement for hVPS34 during M1 muscarinic receptor signaling. Elucidation of the intersections between these distinct pathways will lead to new insights into mast cell degranulation.

* This work was supported by a grant from the Sandler Foundation for Asthma Research (to J. M. B.) and by National Institutes of Health Training Grant T32 DK07513 (to D. A. W.).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 Current address: Integrated Dept. of Immunology, National Jewish Center, Denver, CO 80206.

§ To whom correspondence should be addressed: Dept. of Molecular Pharmacology, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461. Tel.: 718-430-2153; Fax: 718-430-3749; E-mail: Backer@aecom.yu.edu.

Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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