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J. Biol. Chem., Vol. 279, Issue 17, 17570-17577, April 23, 2004

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Ceramide Kinase Is a Mediator of Calcium-dependent Degranulation in Mast Cells^*

Susumu Mitsutake, Tack-Joong Kim, Yuichi Inagaki, Mariko Kato, Toshiyuki Yamashita, and Yasuyuki Igarashi

From the Department of Biomembrane and Biofunctional Chemistry and the Department of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita 12, Nishi 6, Kita-ku, Sapporo 060-0812, Japan

Ceramide kinase (CERK) catalyzes the conversion of ceramide to ceramide 1-phosphate (C1P) and is known to be activated by calcium. Although several groups have examined the functions of CERK and its product C1P, the functions of C1P and CERK are not understood. We studied the RBL-2H3 cell line, a widely used model for mast cells, and found that CERK and C1P are required for activation of the degranulation process in mast cells. We found that C1P formation was enhanced during activation induced by IgE/antigen or by Ca²⁺ ionophore A23187. The formation of C1P required the intracellular elevation of Ca²⁺. We generated RBL-2H3 cells that stably express CERK, and when these cells were treated with A23187, a concomitant C1P formation was observed and degranulation increased 4-fold, compared with mock transfectants. The cell-permeable N-acetylsphingosine (C₂-ceramide), a poor substrate of CERK, inhibited both the formation of C1P and degranulation, indicating that C1P formation was necessary for degranulation. Exogenous introduction of CERK into permeabilized RBL-2H3 cells caused degranulation. We identified a cytosolic localization of CERK that provides exposure to cytosolic Ca²⁺. Taken together, these results indicate that C1P formation is a necessary step in the degranulation pathway in RBL-2H3 cells.

Received for publication, November 25, 2003 , and in revised form, February 4, 2004.

^* This work was supported in part by a Grant-in-aid for Scientific Research on Priority Area (B) 12140201 from the Ministry of Education, Culture, Sport, Science, and Technology, Japan. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Biomembrane and Biofunctional Chemistry, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita 12, Nishi 6, Kita-ku, Sapporo 060-0812, Japan. Tel.: 81-11-706-3970; Fax: 81-11-706-4986; E-mail: yigarash{at}pharm.hokudai.ac.jp.

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