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Thromboxane receptor

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TBXA2R
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesTBXA2R, BDPLT13, TXA2-R, thromboxane A2 receptor
External IDsOMIM: 188070; MGI: 98496; HomoloGene: 825; GeneCards: TBXA2R; OMA:TBXA2R - orthologs
Orthologs
SpeciesHumanMouse
Entrez

6915

21390

Ensembl

ENSG00000006638

ENSMUSG00000034881

UniProt

P21731

P30987

RefSeq (mRNA)

NM_001060
NM_201636

NM_001277265
NM_009325
NM_001358512

RefSeq (protein)

NP_001051
NP_963998

NP_001264194
NP_033351
NP_001345441

Location (UCSC)Chr 19: 3.59 – 3.61 MbChr 10: 81.16 – 81.17 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

The thromboxane receptor (TP) also known as the prostanoid TP receptor is a protein that in humans is encoded by the TBXA2R gene, The thromboxane receptor is one among the five classes of prostanoid receptors[5] and was the first eicosanoid receptor cloned.[6] The TP receptor derives its name from its preferred endogenous ligand thromboxane A2.[5]

The TP receptor is a G-protein coupled receptor coupled to the G protein Gq.[7] The initial purification and cloning of the TP receptor established this protein as a member of the G protein-coupled super family of seven-transmembrane receptors.[8] The gene responsible for the thromboxane receptor, TBXA2R is found on chromosome 19 and spans 15 kilobases.[9]

Heterogeneity

Molecular biology findings have provided definite evidence of human TP receptor subtypes.[5] The originally cloned TP from placenta (343 amino acids in length) is known as the α isoform, and the splice variant cloned from endothelium (with 407 amino acids) is termed the β isoform.[8] The first 328 amino acids are the same for both isoforms, but the β isoform exhibits an extended C-terminal cytoplasmic domain.[8] Both isoforms functionally couple to a Gq protein leading to the phospholipase C activation, calcium release and activation of protein kinase C.[6] Nevertheless, they couple oppositely to adenylate cyclase. TPα activates adenylate cyclase while TPβ inhibits this enzyme.[6] Intrareceptor differences in C-terminal tail sequence also allow for significant differences in their ability to internalize in response to agonist exposure.[10] For example, in HEK-293 cells, TPβ but not TPα undergoes U46619-induced G protein-coupled receptor (GRK) phosphorylation and internalization, whereas the C-terminus of TPα is not capable of being phosphorylated by GRKs.[10]

The expression of α and β isoforms is not equal within or across different cell types.[8] For example, platelets express high concentrations of the α isoform (and possess residual RNA for the β isoform), while expression of the β isoform has not been documented in these cells.[8] The β isoform is expressed in human endothelium.[10]

Tissue distribution

Historically, TP receptor involvement in blood platelet function has received the greatest attention. However, it is now clear that TP receptors exhibit a wide distribution in different cell types and among different organ systems.[8] For example, TP receptors have been localized in cardiovascular, reproductive, immune, pulmonary and neurological tissues, among others.[8]

Organ/Tissue Cells/Cell lines
TP Receptor Distribution[8] Lung, Spleen, Uterus, Placenta, Aorta, Heart, Intestine, Liver, Eye, Thymus, Kidney, Spinal Cord, Brain Platelets, Glomerular mesangial cells, Oligodendrocytes, Cardiac myocytes, Epithelial cells, Hela cells, Smooth muscle cells, Endothelial cells, Trophoblasts, Schwann cells, Astrocytes, Megakaryocytes, Kupffer cells, Human erythroleukemic megakaryocyte (HEL), K562 (Human chronic myelogenous leukemia) cells, Hepatoblastoma HepG2 cells, Immature thymocytes, EL-4 (mouse T cell line)

Biological roles

Over the years, different biological roles for TP receptor signaling have been established in both homeostatic and pathological processes. TP receptor activation is thought to be involved in thrombosis/hemostasis, modulation of the immune response, acute myocardial infarction, inflammatory lung disease, hypertension, nephrotic disease, etc.[8]

Biological roles of TXA2/TP receptor[8]
Asthma

Inflammatory lung disease

Hemostasis/thrombosis

Sickle cell disease

Cardiovascular disease

Lupus nephritis

Acute myocardial infarction

Nephrotic syndrome, Hypertension

Immune complex glomerulonephritis

Pregnancy-induced hypertension (PIH)

Regulating acquired immunity

Chronic inflammation in atopic diseases

Chronic inflammatory bowel diseases

Antagonists

TP receptor has been the easiest of the prostanoids receptors to block.[5] Several laboratories have synthesized and developed TP receptor antagonists such as Seratrodast (AA-2414), Terutroban (S18886), PTA2, 13-APA, GR-32191, Sulotroban (BM-13177), SQ-29,548, SQ-28,668, ONO-3708, Bay U3405, EP-045, BMS-180,291, S-145 etc. which belong to numerous structural classes.[5][11] TP receptor antagonists have been evaluated as potential therapeutic agents for asthma, thrombosis and hypertension.[11] Some studies have in fact revealed that TP receptor antagonists are more effective than thromboxane synthase inhibitors.[11]

See also

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000006638 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000034881 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ a b c d e Devillier P, Bessard G (1997). "Thromboxane A2 and related prostaglandins in airways". Fundam Clin Pharmacol. 11 (1): 2–18. doi:10.1111/j.1472-8206.1997.tb00163.x. PMID 9182072.
  6. ^ a b c Rolin S, Masereel B, Dogné JM (March 2006). "Prostanoids as pharmacological targets in COPD and asthma". Eur J Pharmacol. 533 (1–3): 89–100. doi:10.1016/j.ejphar.2005.12.058. PMID 16458293.
  7. ^ Abe T, Takeuchi K, Takahashi N, Tsutsumi E, Taniyama Y, Abe K (1995). "Rat kidney thromboxane receptor: molecular cloning, signal transduction, and intrarenal expression localization". J. Clin. Invest. 96 (2): 657–64. doi:10.1172/JCI118108. PMC 185246. PMID 7635958.
  8. ^ a b c d e f g h i j Huang JS, Ramamurthy SK, Lin X, Le Breton GC (May 2004). "Cell signalling through thromboxane A2 receptors". Cell Signal. 16 (5): 521–33. doi:10.1016/j.cellsig.2003.10.008. PMID 14751539.
  9. ^ TBXA2R thromboxane A2 receptor (Homo sapiens)
  10. ^ a b c Farooque SP, Arm JP, Lee TH (2008). "Lipid Mediators: Leukotrienes, Prostanoids, Lipoxins, and Platelet-Activating Factor". In Holt PG, Kaplan AP, Bousquet J (eds.). Allergy and Allergic Diseases. Vol. 1 (2 ed.). Oxford, UK: Wiley-Blackwell. ISBN 1-4051-5720-8.
  11. ^ a b c Shen RF, Tai HH (1998). "Thromboxanes: synthase and receptors". J Biomed Sci. 5 (3): 153–72. doi:10.1007/BF02253465. PMID 9678486.
  • "Prostanoid Receptors: TP". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.

Further reading

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