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 BLT1 (originally termed BLT). 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 to 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. This is the first example of 'PROMOTER IN ORF' in mammals. BLT2 is expressed ubiquitously, in contrast to BLT1 that is expressed predominantly in leukocytes. Chinese hamster ovary cells expressing BLT2 exhibit LTB4-induced chemotaxis, calcium mobilization, and pertusis-toxin-insensitive inhibition of adenylyl cyclase. Several BLT1 antagonists, including U75302, 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 anti-inflammatory therapeutic and promises to expand our knowledge of LTB4 function. The location of the gene suggests shared transcriptional regulation of these two receptors. Here we propose a novel classification of leukotriene receptors.
1)Yokomizo, T., Kato, K., Terawaki, K., Izumi, T., and Shimizu, T. A second leukotriene B4 receptor, BLT2: a new therapeutic target in inflammation and immunological disorders. J. Exp. Med. (2000) 192: p421-432
2)Kato, K., Yokomizo, T., Izumi, T., and Shimizu, T. Cell-specific transcriptional regulation of human leukotriene B4 receptor gene. J. Exp. Med. (2000) 192: p413-420
3)Noiri, E., T. Yokomizo, A. Nakao, T. Izumi, T. Fujita, S. Kimura, and T. Shimizu. 2000. A novel in vivo approach showing the chemotactic activity of leukotriene B4 in acute renal ischemic-reperfusion injury. Proc. Natl. Aca. Sci. U.S.A. (2000) 97:p823-828.
4)Yokomizo, T., Izumi, T., Chang, K., Takuwa, Y., and Shimizu, T. A G-protein coupled receptor for leukotriene B4 that mediates chemotaxis. Nature (1997) 387 p620-624
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