12-Hydroxyheptadecatrienoic acid promotes epidermal wound healing by accelerating keratinocyte migration via the BLT2 receptor.

Leukotriene B4 (LTB4) receptor type 2 (BLT2) is a G protein-coupled receptor (GPCR) for 12(S)-hydroxyheptadeca-5Z,8E,10E-trienoic acid (12-HHT) and LTB4. Despite the well-defined proinflammatory roles of BLT1, the in vivo functions of BLT2 remain elusive. As mouse BLT2 is highly expressed in epidermal keratinocytes, we investigated the role of the 12-HHT/BLT2 axis in skin wound healing processes.

Thromboxane A synthase-independent production of 12-hydroxyheptadecatrienoic acid, a BLT2 ligand.

12(S)-hydroxyheptadeca-5Z,8E,10E-trienoic acid (12-HHT) has long been considered a by-product of thromboxane A₂ (TxA₂) biosynthesis with no biological activity. Recently, we reported 12-HHT to be an endogenous ligand for BLT2, a low-affinity leukotriene B4 receptor. To delineate the biosynthetic pathway of 12-HHT, we established a method that enables us to quantify various eicosanoids and 12-HHT using LC-MS/MS analysis.

Leukotriene B4 receptor BLT2 negatively regulates allergic airway eosinophilia.

Leukotriene B4 (LTB4) has been implicated in the pathogenesis of allergic diseases. BLT2, a low-affinity LTB4 receptor, is activated by LTB4 and 12(S)-hydroxyheptadeca-5Z,8E,10E-trienoic acid (12-HHT). Although the high-affinity LTB4 receptor BLT1 has been shown to exert proinflammatory roles, the role of BLT2 in allergic inflammation has not been clarified.

Helix 8 of leukotriene B4 receptor 1 inhibits ligand-induced internalization.

Recent crystallographic studies revealed that G-protein-coupled receptors (GPCRs) possess a putative cytoplasmic helical domain, termed helix 8, at the proximal region of the C-terminal tail. However, the significance of helix 8 in GPCR functions and signaling is not fully understood. Helix 8 mutants of leukotriene B4 receptor type 1 (BLT1) exhibit prolonged activation after ligand stimulation, suggesting some regulatory roles of helix 8 in GPCR signaling.