A G protein-coupled receptor for the 5(S),12(R)-dihydroxy metabolite of aracidonic acid, Leukotriene B4, vis., Leukotriene B4 receptor 2 (BLT2), but not its Leukotriene B4 receptor 1, mediates responses to 12(S)-HETE, 12(R)-HETE, and 12-oxo-ETE in many cell types. Based on the effects of LTB4 receptor antagonists, for example, leukotriene B4 receptor 2 mediates: the rise in cytosolic Ca2+ concentration (a key signal for cell activation) in human neutrophils and the rise in cytosolic Ca2+ concentration and chemotaxis in Chinese hamstery ovarian cells stimulated by 12(S)-HETE, 12(R)-HETE, and/or 12-oxo-ETE; the itch response to 12(S)-HETE and PMN inflammatory infiltration response to 12(R)-HETE triggered by the injection these metabolites into the skin of  mice and guinea pigs, respectively; and an in vitro angiogenic response by Human umbilical vein endothelial cells (HUVEC) and in vivo angiogenic response by mice to 12(S)-HETE. The BLT2 receptor, in contrast to the GPR31 receptor, appears to be expressed at a high level in a wide range of tissues including neutrophils, eosinophils, monocytes, spleen, liver, and ovary.  However, 12-Hydroxyheptadecatrienoic acid (i.e. 12-(S)-hydroxy-5Z,8E,10E-heptadecatrienoic acid or 12-HHT), a product made when prostaglandin H2 is metabolized to Thromboxane A2 by Thromboxane synthase or spontaneously rearranges non-enzymatically (see 12-Hydroxyheptadecatrienoic acid) is the most potent BLT2 receptor agonist detected to date.  To clarify the role of BLT2 versus GPC31 receptors in responses to 12(S)-HETE, and the role(s) of LTB4, 12(S)-HETE, versus 12-HHT in BLT2-mediated responses, it will be necessary to determine: a) if leukotriene B4 interacts with the GPR31 receptor; b) if BLT2 receptor antagonists interfere with the GPR31 receptor; and c) the relative concentrations and availability of LTB4, 12(S)-HETE, and 12-HHT in tissues exhibiting BLT2-dependent responses.  Ultimately, both receptors and all three ligands may prove to be responsible for some tissue responses in vivo.