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BLT2 receptor

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Immunopharmacology Ligand  Target has curated data in GtoImmuPdb

Target id: 268

Nomenclature: BLT2 receptor

Family: Leukotriene receptors

Gene and Protein Information Click here for help
class A G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 358 14q12 LTB4R2 leukotriene B4 receptor 2 8,12,18
Mouse 7 360 14 C3 Ltb4r2 leukotriene B4 receptor 2 7
Rat 7 358 15p13 Ltb4r2 leukotriene B4 receptor 2
Gene and Protein Information Comments
In humans, a longer form of BLT2 is 389 amino acids long.
Previous and Unofficial Names Click here for help
BLTR2 | LTB4 receptor JULF2 | LTB4-R2 | 12-HHT receptor | NOP9
Database Links Click here for help
Specialist databases
GPCRDB lt4r2_human (Hs), lt4r2_mouse (Mm), lt4r2_rat (Rn)
Other databases
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
Pharos
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Natural/Endogenous Ligands Click here for help
12-epi LTB4
12-hydroxyheptadecatrienoic acid
20-hydroxy-LTB4
LTB4
12R-HETE
15S-HETE
12S-HETE
12S-HPETE
Comments: 12-Hydroxyheptadecatrienoic acid is the most potent endogenous agonist
Potency order of endogenous ligands
12-hydroxyheptadecatrienoic acid > LTB4 > 12S-HETE = 12S-HPETE > 15S-HETE > 12R-HETE > 20-hydroxy-LTB4  [13,17]

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Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
LTB4 Small molecule or natural product Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Immunopharmacology Ligand Hs Partial agonist 7.6 pKd 18
pKd 7.6 (Kd 2.27x10-8 M) [18]
CAY10583 Small molecule or natural product Mm Full agonist 8.5 pKi 7
pKi 8.5 (Ki 3x10-9 M) [7]
12-hydroxyheptadecatrienoic acid Small molecule or natural product Ligand is endogenous in the given species Hs Full agonist 7.7 pEC50 13
pEC50 7.7 (EC50 1.9x10-8 M) [13]
CAY10583 Small molecule or natural product Hs Full agonist 7.7 pEC50 7
pEC50 7.7 (EC50 2x10-8 M) [7]
15S-HETE Small molecule or natural product Ligand is endogenous in the given species Hs Partial agonist <7.5 pEC50 17
pEC50 <7.5 (EC50 >3x10-8 M) [17]
12S-HETE Small molecule or natural product Ligand is endogenous in the given species Hs Partial agonist <7.5 pEC50 17
pEC50 <7.5 (EC50 >3x10-8 M) [17]
12-epi LTB4 Small molecule or natural product Ligand is endogenous in the given species Hs Partial agonist <7.5 pEC50 17
pEC50 <7.5 (EC50 >3x10-8 M) [17]
LTB4 Small molecule or natural product Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Immunopharmacology Ligand Hs Partial agonist 6.8 pEC50 13
pEC50 6.8 (EC50 1.42x10-7 M) [13]
CP-195543 Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Partial agonist <5.0 pEC50 17
pEC50 <5.0 (EC50 >1x10-5 M) [17]
12-hydroxyheptadecatrienoic acid Small molecule or natural product Ligand is endogenous in the given species Hs Full agonist 8.6 pIC50 13
pIC50 8.6 (IC50 2.8x10-9 M) [13]
LTB4 Small molecule or natural product Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Immunopharmacology Ligand Hs Partial agonist 7.6 pIC50 13
pIC50 7.6 (IC50 2.5x10-8 M) [13]
View species-specific agonist tables
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
LY255283 Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Antagonist 6.0 – 7.1 pIC50 4,17
pIC50 6.0 – 7.1 (IC50 1x10-6 – 8.7x10-8 M) [4,17]
CP-195543 Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Antagonist 6.0 pIC50 17
pIC50 6.0 (IC50 1x10-6 M) [17]
ZK-158252 Small molecule or natural product Hs Antagonist 6.0 pIC50 17
pIC50 6.0 (IC50 1x10-6 M) [17]
Antagonist Comments
Currently, LY255283 is used as a BLT2-specific antagonist, but this compound also inhibits BLT1 in a non-competitive manner. [11].
Immunopharmacology Comments
The human BLT2 receptor is the low affinity leukotriene B4 receptor, and may be involved in maintaining intestinal barrier function (leading to colitis) and eosinophilic airway inflammation. BLT2 receptor is considered to be the principal mediator of leukotriene B4 effects in synovial tissues from patients with rheumatoid arthritis [3].
Immuno Process Associations
Immuno Process:  Inflammation
GO Annotations:  Associated to 1 GO processes
GO:0006954 inflammatory response IBA
Immuno Disease Associations
Disease Name:  Rheumatoid arthritis
Disease Synonyms:  no synonynms
Comment:  The expression of LTB4R (BLT1) and LTB4R2 (BLT2) mRNA is elevated in synovial tissues of RA patients compared to OA patients., with LTB4R2 > LTB4R. LTB4R2 is the principal mediator of leukotriene B4 effects in RA synovial tissues.
Disease X-refs:  Disease Ontology: DOID:7148
OMIM: 180300
References:  3
Primary Transduction Mechanisms Click here for help
Transducer Effector/Response
Gi/Go family Adenylyl cyclase inhibition
References:  8,12,18
Secondary Transduction Mechanisms Click here for help
Transducer Effector/Response
Gq/G11 family Phospholipase C stimulation
References:  8,12,18
Tissue Distribution Click here for help
Atherosclerotic lesions
Species:  Human
Technique:  Immunohistochemistry
References:  2
Synovial tissues derived from patients with rheumatoid arthritis
Species:  Human
Technique:  in situ hybridisation
References:  3
Abdominal aortic aneurysms
Species:  Human
Technique:  Immunohistochemistry
References:  5
Spleen, liver, ovary, and leukocytes
Species:  Human
Technique:  Northern blot
References:  18
Small intestine and skin
Species:  Mouse
Technique:  Northern blot
References:  7
Expression Datasets Click here for help

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Log average relative transcript abundance in mouse tissues measured by qPCR from Regard, J.B., Sato, I.T., and Coughlin, S.R. (2008). Anatomical profiling of G protein-coupled receptor expression. Cell, 135(3): 561-71. [PMID:18984166] [Raw data: website]

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Functional Assays Click here for help
CHO cells transfected with the human BLT2 receptor
Species:  Human
Tissue: 
Response measured:  Chemotaxis
References:  18
CHO cells transfected with the human BLT2 receptor
Species:  Human
Tissue: 
Response measured:  Increase in intracellular calcium
References:  13
MDCK cells trasnfected with human BLT2 receptor
Species:  Human
Tissue: 
Response measured:  Increase in transendothelial resistance
References:  6
Physiological Functions Click here for help
Chemotaxis
Species:  Mouse
Tissue:  Macrophages
References:  15
Angiogenesis
Species:  Mouse
Tissue:  Vasculature
References:  9
Chemotaxis
Species:  Mouse
Tissue:  Mast cells
References:  13
Physiological Consequences of Altering Gene Expression Click here for help
Transgenic mice overexpressing the rat BLT2R under the CAG promoter exhibit an increased increased blood vessel formation in response to LTB4 and 12(S)-HETE.
Species:  Mouse
Tissue:  Ubiquitous expression profile
Technique:  Targeting in embryonic stem cells-rat BLT2R transgene injected embryos
References:  10
BLT2 receptor knockout mice exhibit more severe colitis in response to dextran sodium sulfate (DSS) compared with that in either WT or BLT1R knockout mice, which was accompanied by increased expression of inflammatory cytokines, chemokines, and MMPs.
Species:  Mouse
Tissue:  Colon
Technique:  Insertion into the open reading frame of the BLT2 gene
References:  6
BLT2 receptor knockout mice exhibit attenuated allergic airway eosinophilia compared with WT mice, which was accompanied by reduced IL-13 production in CD4-positive T cells.
Species:  Mouse
Tissue:  T cells
Technique:  Insertion into the open reading frame of the BLT2 gene
References:  11
Phenotypes, Alleles and Disease Models Click here for help Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Ltb4r1/Ltb4r2tm2Bodd Ltb4r1/Ltb4r2tm2Bodd/Ltb4r1/Ltb4r2tm2Bodd
involves: 129S4/SvJaeSor * C57BL/6
MGI:1888501  MP:0003436 decreased susceptibility to induced arthritis PMID: 16670336 
Ltb4r1/Ltb4r2tm2Bodd|Ltb4r2+ Ltb4r1/Ltb4r2tm2Bodd/Ltb4r2+
involves: 129S4/SvJaeSor * C57BL/6
MGI:1888501  MP:0003436 decreased susceptibility to induced arthritis PMID: 16670336 
Ltb4r2tm1Bodd Ltb4r2tm1Bodd/Ltb4r2tm1Bodd
involves: 129S4/SvJaeSor * C57BL/6
MGI:1888501  MP:0003436 decreased susceptibility to induced arthritis PMID: 20656922 
Ltb4r1/Ltb4r2tm2Bodd Ltb4r1/Ltb4r2tm2Bodd/Ltb4r1/Ltb4r2tm2Bodd
involves: 129S4/SvJaeSor * C57BL/6
MGI:1888501  MP:0008720 impaired neutrophil migration PMID: 20656922 
Biologically Significant Variants Click here for help
Type:  Single nucleotide polymorphism
Species:  Human
Description:  G+514T and C+1165G polymorphism of the LTB4R and LTB4R2 genes have been associated with an increased risk of stroke. In addition, C+1434A and C+3886T were associated with the cardioembolic subtype of stroke. The close proximity of the genes encoding those receptors suggests that those polymorphisms cannot be ascribed to either of the genes alone.
References:  1
General Comments
The open reading frame of BLT2 was identified during the analysis of the promoter of BLT1, a high affinity receptor for leukotriene B4 [16]. HEK and CHO cells trasnfected with BLT2 cDNA exhibited a low affinity to LTB4, thus this receptor was named as BLT2 [18]. BLT2 was also activated by various other hydroxy fatty acids including 12-epi LTB4, 12S-HETE and 15S-HETE [17]. Search for endogenous high affinity ligands for BLT2 resulted in the identification of 12-HHT (12(S)-Hydroxyheptadeca-5Z, 8E, 10E-trienoic acid), previously known as a by-product of thromboxane A2 biosynthesis, as a high-affinity BLT2 ligand [13]. BLT2 is expressed ubuiquitously in human [18], and in small intestine, colon and skin in mice [7]. Mice deficient in both BLT1 and BLT2 showed reduced disease severity in an arthritis model [14]. BLT2-deficient mice with intact BLT1 showed more severe colitis induced by dextran sulfate, possibly due to the loss of intestinal barrier function maintained by BLT2 [6]. BLT2-deficient mice also showed severe eosinophilic inflammation induced by sensitization and elicitation by ovalubumin accompanied by the reduced accumulation of interleukin-13 in the allergic airway [11].

References

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1. Bevan S, Dichgans M, Wiechmann HE, Gschwendtner A, Meitinger T, Markus HS. (2008) Genetic variation in members of the leukotriene biosynthesis pathway confer an increased risk of ischemic stroke: a replication study in two independent populations. Stroke, 39 (4): 1109-14. [PMID:18323512]

2. Bäck M, Bu DX, Bränström R, Sheikine Y, Yan ZQ, Hansson GK. (2005) Leukotriene B4 signaling through NF-kappaB-dependent BLT1 receptors on vascular smooth muscle cells in atherosclerosis and intimal hyperplasia. Proc Natl Acad Sci USA, 102 (48): 17501-6. [PMID:16293697]

3. Hashimoto A, Endo H, Hayashi I, Murakami Y, Kitasato H, Kono S, Matsui T, Tanaka S, Nishimura A, Urabe K et al.. (2003) Differential expression of leukotriene B4 receptor subtypes (BLT1 and BLT2) in human synovial tissues and synovial fluid leukocytes of patients with rheumatoid arthritis. J Rheumatol, 30 (8): 1712-8. [PMID:12913925]

4. Herron DK, Goodson T, Bollinger NG, Swanson-Bean D, Wright IG, Staten GS, Thompson AR, Froelich LL, Jackson WT. (1992) Leukotriene B4 receptor antagonists: the LY255283 series of hydroxyacetophenones. J Med Chem, 35 (10): 1818-28. [PMID:1316967]

5. Houard X, Ollivier V, Louedec L, Michel JB, Bäck M. (2009) Differential inflammatory activity across human abdominal aortic aneurysms reveals neutrophil-derived leukotriene B4 as a major chemotactic factor released from the intraluminal thrombus. FASEB J, 23 (5): 1376-83. [PMID:19136615]

6. Iizuka Y, Okuno T, Saeki K, Uozaki H, Okada S, Misaka T, Sato T, Toh H, Fukayama M, Takeda N et al.. (2010) Protective role of the leukotriene B4 receptor BLT2 in murine inflammatory colitis. FASEB J, 24 (12): 4678-90. [PMID:20667973]

7. Iizuka Y, Yokomizo T, Terawaki K, Komine M, Tamaki K, Shimizu T. (2005) Characterization of a mouse second leukotriene B4 receptor, mBLT2: BLT2-dependent ERK activation and cell migration of primary mouse keratinocytes. J Biol Chem, 280 (26): 24816-23. [PMID:15866883]

8. Kamohara M, Takasaki J, Matsumoto M, Saito T, Ohishi T, Ishii H, Furuichi K. (2000) Molecular cloning and characterization of another leukotriene B4 receptor. J Biol Chem, 275 (35): 27000-4. [PMID:10889186]

9. Kim GY, Lee JW, Cho SH, Seo JM, Kim JH. (2009) Role of the low-affinity leukotriene B4 receptor BLT2 in VEGF-induced angiogenesis. Arterioscler Thromb Vasc Biol, 29 (6): 915-20. [PMID:19286633]

10. Mathis SP, Jala VR, Lee DM, Haribabu B. (2010) Nonredundant roles for leukotriene B4 receptors BLT1 and BLT2 in inflammatory arthritis. J Immunol, 185 (5): 3049-56. [PMID:20656922]

11. Matsunaga Y, Fukuyama S, Okuno T, Sasaki F, Matsunobu T, Asai Y, Matsumoto K, Saeki K, Oike M, Sadamura Y et al.. (2013) Leukotriene B4 receptor BLT2 negatively regulates allergic airway eosinophilia. FASEB J, 27 (8): 3306-14. [PMID:23603839]

12. Nilsson NE, Tryselius Y, Owman C. (2000) Genomic organization of the leukotriene B(4) receptor locus of human chromosome 14. Biochem Biophys Res Commun, 274 (2): 383-8. [PMID:10913347]

13. Okuno T, Iizuka Y, Okazaki H, Yokomizo T, Taguchi R, Shimizu T. (2008) 12(S)-Hydroxyheptadeca-5Z, 8E, 10E-trienoic acid is a natural ligand for leukotriene B4 receptor 2. J Exp Med, 205 (4): 759-66. [PMID:18378794]

14. Shao WH, Del Prete A, Bock CB, Haribabu B. (2006) Targeted disruption of leukotriene B4 receptors BLT1 and BLT2: a critical role for BLT1 in collagen-induced arthritis in mice. J Immunol, 176 (10): 6254-61. [PMID:16670336]

15. Subbarao K, Jala VR, Mathis S, Suttles J, Zacharias W, Ahamed J, Ali H, Tseng MT, Haribabu B. (2004) Role of leukotriene B4 receptors in the development of atherosclerosis: potential mechanisms. Arterioscler Thromb Vasc Biol, 24 (2): 369-75. [PMID:14656734]

16. Yokomizo T, Izumi T, Chang K, Takuwa Y, Shimizu T. (1997) A G-protein-coupled receptor for leukotriene B4 that mediates chemotaxis. Nature, 387 (6633): 620-4. [PMID:9177352]

17. Yokomizo T, Kato K, Hagiya H, Izumi T, Shimizu T. (2001) Hydroxyeicosanoids bind to and activate the low affinity leukotriene B4 receptor, BLT2. J Biol Chem, 276 (15): 12454-9. [PMID:11278893]

18. Yokomizo T, Kato K, Terawaki K, Izumi T, Shimizu T. (2000) A second leukotriene B(4) receptor, BLT2. A new therapeutic target in inflammation and immunological disorders. J Exp Med, 192 (3): 421-32. [PMID:10934230]

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