Leukotriene B4 receptor 2, also known as BLT2, BLT2 receptor, and BLTR2, is an Integral membrane protein that is encoded by the LTB4R2 gene in humans and the Ltbr2 gene in mice. Discovered several years after the leukotriene B4 receptor 1 (BLT1), BLT2 receptor binds leukotriene B4 (LTB4) with far lower affinity than the BLT1 receptor does and therefore has been termed the low affinity LTB4 receptor. Sometime after its initial discovery, the BLT2 receptor was shown to bind and become activated by several other arachidonic acid metabolites, one of which, 12-hydroxyheptadecatrienoic acid (12-HHT), has 10- to 100-fold higher affinity for it than does LTB4; 12-HHT fails to bind or activate BLT1 receptors. While BLT2 receptors have some actions similar to BLT1 receptors, they have other actions which clearly oppose those of BLT1 in regulating inflammation and allergic responses; BLT2 receptors also have actions that extend beyond those of BLT1 receptors. Laboratory, animal, and other pre-clinical studies suggest that BLT2 receptors may be involved not only in inflammation and allergy but also in human cancer.
Function BLT2 is a cell surface receptor that functions by recognizing, binding, and mediating responses to a particular set of messenger molecules or ligands. These messenger ligands are any one of a range of structurally different arachidonic acid metabolites made and released by nearby cells to act as paracrine signals for coordinating responses between cells or autocrine signals for modulating their parent cells' responses.
Genes Several years after their identification of a leukotriene B4 (LTB4) receptor termed BLT1 or BLTR1 and encoded by the LTB4R1 gene, Shimizu and colleagues identified a second LTB4 receptor, BLT2 or BLTR2, encoded by the LTB4R2 gene. LTBR1 and LTBR2 encode for proteins with 45% amino acid identity that belong to the G protein-coupled receptor superfamily. The two genes form a cluster on human and mouse chromosome 14; in humans but not mice, this cluster has a very unusual configuration in that LTBR2's open reading frame overlaps the promoter and 5' untranslated region of LTBR1. The significance of this overlap is not known. Monkeys, rats, and dogs have also been shown to express LTB4R2 orthologs. Two BLT2-like receptors, Blt2a and Blt2b, with 49% amino acid identity to each other and 34% and 29%, respectively, amino acid identities to human BLT2 have been cloned from zebrafish embryos. The latter citation presents a phylogenic tree on the amino acid relatedness of these two receptors as well as those from humans, monkeys, dogs, rats and mice to each other.
Mechanism of action BLT2 receptors, similar to BLT1 receptors, are G protein-coupled receptors that, when ligand-bound, activate G proteins that contain either the Gi alpha subunit and are therefore inhibited by pertussis toxin or the Gq alpha subunit and therefore not inhibited by pertussis toxin. (Pertussis toxin sensitivity is an imported test for G protein receptor linkages.) BLT2 receptors stimulate cells to transiently elevated cytosolic calcium ion concentrations, thereby activating calcium-activated intracellular signaling molecules; it also stimulates cells to activate extracellular signal-regulated kinases (ERKs), protein kinase B (also known as Akt), c-Jun N-terminal kinases (JNKs), Janus kinase (JAK)-STAT protein (i.e. signal transducer and activator of transcription), NADPH oxidase (NOX), and NF-κB pathways. One prominent cell-activating pathway involves BLT2 receptor activation of NOX2 or NOX1 with the subsequent production of reactive oxygen species which in turn activate the transcription inducing function of NF-κB.
Tissue distribution The human BLT2 receptor is expressed in a wide range of tissues including spleen, blood leukocytes, liver, ovary, pancreas, heart, prostate gland, testes, small intestine, kidney, lung, colon, thymus, muscle, and placenta; this contrasts with the BLT1 receptor which appears to have a more limited expression pattern including mainly circulating blood leukocytes and lymphocytes. The mouse Blt2 receptor also shows a more limited distribution pattern than the human BLT2 receptor, showing appreciable expression in the small intestine and skin, and low expression in the colon and spleen.
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