The Journal of Experimental Medicine
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Published online 8 August 2000.
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© The Rockefeller University Press, 0022-1007/2000/8/421/ $5.00
The Journal of Experimental Medicine, Volume 192, Number 3, August 7, 2000 421-432

Original Article

A Second Leukotriene B4 Receptor, BLT2: A New Therapeutic Target in Inflammation and Immunological Disorders

Takehiko Yokomizoa,b, Kazuhiko Katoa,c, Kan Terawakia,b, Takashi Izumia,b, and Takao Shimizua,b
a Department of Biochemistry and Molecular Biology, Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
b Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Corporation, Tokyo 113-0033, Japan
c Pharmaceutical Research Center, Meiji Seika Kaisha, Limited, Yokohama 222-8567, Japan

Correspondence to: Takao Shimizu, Department of Biochemistry and Molecular Biology, Faculty of Medicine, The 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:tshimizu{at}m.u-tokyo.ac.jp.

Leukotriene B4 (LTB4) is a potent chemoattractant and activator of both granulocytes and macrophages. The actions of LTB4 appear to be mediated by a specific G protein–coupled receptor (GPCR) BLT1, originally termed BLT (Yokomizo, T., T. Izumi, K. Chang, Y. Takuwa, and T. Shimizu. 1997. Nature. 387:620–624). Here, we report the molecular cloning of a novel GPCR for LTB4, designated BLT2, which binds LTB4 with a Kd value of 23 nM compared with 1.1 nM for BLT1, but still efficiently transduces intracellular signaling. BLT2 is highly homologous to BLT1, with an amino acid identity of 45.2%, and its open reading frame is located in the promoter region of the BLT1 gene. BLT2 is expressed ubiquitously, in contrast to BLT1, which is expressed predominantly in leukocytes. Chinese hamster ovary cells expressing BLT2 exhibit LTB4-induced chemotaxis, calcium mobilization, and pertussis toxin–insensitive inhibition of adenylyl cyclase. Several BLT1 antagonists, including U 75302, failed to inhibit LTB4 binding to BLT2. Thus, BLT2 is a pharmacologically distinct receptor for LTB4, and may mediate cellular functions in tissues other than leukocytes. BLT2 provides a novel target for antiinflammatory therapy and promises to expand our knowledge of LTB4 function. The location of the gene suggests shared transcriptional regulation of these two receptors.

Key Words: BLT, cloning, gene cluster, leukotriene, low-affinity receptor


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