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Protease-activated receptor

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coagulation factor II thrombin receptor
Identifiers
SymbolF2R
Alt. symbolsTR; HTR; CF2R; PAR1; PAR-1
NCBI gene2149
HGNC3537
OMIM187930
PDB3BEF
RefSeqNM_001992
UniProtP25116
Other data
LocusChr. 5 q13.3
Search for
StructuresSwiss-model
DomainsInterPro
F2R like trypsin receptor 1
Identifiers
SymbolF2RL1
Alt. symbolsPAR2, GPR11
NCBI gene2150
HGNC3538
OMIM600933
PDB5NDD
RefSeqNM_005242
UniProtP55085
Other data
LocusChr. 5 q13.3
Search for
StructuresSwiss-model
DomainsInterPro
coagulation factor II thrombin receptor like 2
Identifiers
SymbolF2RL2
Alt. symbolsPAR3; PAR-3
NCBI gene2151
HGNC3539
OMIM601919
PDB2PUX
RefSeqNM_004101
UniProtO00254
Other data
LocusChr. 5 q13.3
Search for
StructuresSwiss-model
DomainsInterPro
F2R like thrombin or trypsin receptor 3
Identifiers
SymbolF2RL3
Alt. symbolsPAR4
NCBI gene9002
HGNC3540
OMIM602779
PDB2PV9
RefSeqNM_003950
UniProtQ96RI0
Other data
LocusChr. 19 p13.11
Search for
StructuresSwiss-model
DomainsInterPro

Protease-activated receptors (PAR) are a subfamily of related G protein-coupled receptors that are activated by cleavage of part of their extracellular domain. They are highly expressed in platelets, and also on endothelial cells, myocytes and neurons.[1]

Classification

There are four mammalian members of the protease-activated receptor (PAR) family: PAR1 - encoded by the gene F2R, PAR2 - F2RL1, PAR3 - F2RL2 and PAR4 - F2RL3, all these genes have their locus on chromosome 5 except of PAR4, which is on chromosome 19. They are also members of the seven-transmembrane G-protein-coupled receptor superfamily, and are expressed throughout the body.[2]

History

PAR1 was firstly described in 1991 on human platelets as a thrombin receptor.[3] In 1994 another member of this family was discovered, S. Nystedt named it simply proteinase activated receptor 2.[4] Experiments on F2R knockout mice then led to the discovery of PAR3[5] and PAR4.[6]

Activation

Protease activated receptors are integral membrane proteins that are coupled to G-proteins and are activated by specific cleavage of the amino terminal sequence that exposes a new N-terminal sequence functions as a tethered ligand, which bind a conserved region on extracellular loop 2 (ECL2). Such bound causes the specific change in conformation of the PAR and alters the affinity for intracellular G-protein.[2] Four types of PAR receptors have been identified by molecular cloning, and classified according to the main enzyme that is able to activate it. It has been determined that a large group of proteases cleave and activate PARs receptors, including various endogenous proteases from: a) the coagulation cascade, b) inflammatory cells, and c) the digestive tract. On the other hand PARs can be specifically cleaved and irreversibly activated even by exogenous proteases originetd from insects, bacteria or plants and fungi.[2] The wide distribution of PARs in a variety of cells supports the idea that they are involved in many process related with the gastrointestinal physiology.[7] Although the proteolysis is the main mechanism for PAR activation, it is well known that a synthetic peptide (SLIGKV) that mimics the new N-terminal sequence produced after the cleavage, activates PAR-2 receptors without its proteolytic processing. In this sense, here we report that TFF3 isolated from human breast milk activates PAR-2 receptors of intestinal epithelial cells HT-29. These findings suggest that TFF3 activates intestinal epithelial cells through G-protein-coupled PAR-2, and could actively participate in the immune system of breastfed babies inducing the production of peptides related to innate defense, such as defensins and cytokines.[7]

PARs are activated by the action of serine proteases such as thrombin (acts on PARs 1, 3 and 4) and trypsin (PAR 2).[8] These enzymes cleave the N-terminus of the receptor, which in turn acts as a tethered ligand. In the cleaved state, part of the receptor itself acts as the agonist, causing a physiological response.

Most of the PAR family act through the actions of G-proteins i (cAMP inhibitory), 12/13 (Rho and Ras activation) and q (calcium signalling) to cause cellular actions.

Function

The cellular effects of thrombin are mediated by protease-activated receptors (PARs). Thrombin signalling in platelets contributes to hemostasis and thrombosis. Endothelial PARs participate in the regulation of vascular tone and permeability while in vascular smooth muscle they mediate contraction, proliferation, and hypertrophy. In endothelial cells PARs play a key role in promotion vascular barrier function as they provide a positive signals for endothelial adhesion molecules (vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1(ICAM-1), and E-selectin).[9] PARs contribute to the pro-inflammatory response. For example PAR4 induces leukocyte migration and PAR2 helps macrophages to produce cytokines such as interleukin-8 (IL-8). Recent research has also implicated these novel receptors in muscle growth and bone cell differentiation and proliferation.[2]


See also

References

  1. ^ Macfarlane SR, Seatter MJ, Kanke T, Hunter GD, Plevin R (June 2001). "Proteinase-activated receptors" (abstract). Pharmacological Reviews. 53 (2): 245–82. PMID 11356985.
  2. ^ a b c d Heuberger, Dorothea M.; Schuepbach, Reto A. (December 2019). "Protease-activated receptors (PARs): mechanisms of action and potential therapeutic modulators in PAR-driven inflammatory diseases". Thrombosis Journal. 17 (1): 4. doi:10.1186/s12959-019-0194-8. ISSN 1477-9560. PMC 6440139. PMID 30976204.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  3. ^ Vu, Thien-Khai H.; Hung, David T.; Wheaton, Virginia I.; Coughlin, Shaun R. (March 1991). "Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation". Cell. 64 (6): 1057–1068. doi:10.1016/0092-8674(91)90261-v. ISSN 0092-8674.
  4. ^ Nystedt, S.; Emilsson, K.; Wahlestedt, C.; Sundelin, J. (1994-09-27). "Molecular cloning of a potential proteinase activated receptor". Proceedings of the National Academy of Sciences. 91 (20): 9208–9212. doi:10.1073/pnas.91.20.9208. ISSN 0027-8424. PMC 44781. PMID 7937743.
  5. ^ Ishihara, Hiroaki; Connolly, Andrew J.; Zeng, Dewan; Kahn, Mark L.; Wu Zheng, Yao; Timmons, Courtney; Tram, Tracy; Coughlin, Shaun R. (April 1997). "Protease-activated receptor 3 is a second thrombin receptor in humans". Nature. 386 (6624): 502–506. doi:10.1038/386502a0. ISSN 0028-0836.
  6. ^ Xu, W.-f.; Andersen, H.; Whitmore, T. E.; Presnell, S. R.; Yee, D. P.; Ching, A.; Gilbert, T.; Davie, E. W.; Foster, D. C. (1998-06-09). "Cloning and characterization of human protease-activated receptor 4". Proceedings of the National Academy of Sciences. 95 (12): 6642–6646. doi:10.1073/pnas.95.12.6642. ISSN 0027-8424.
  7. ^ a b Barrera GJ, Tortolero GS (2016). "Trefoil factor 3 (TFF3) from human breast milk activates PAR-2 receptors, of the intestinal epithelial cells HT-29, regulating cytokines and defensins". Bratislavske Lekarske Listy. 117 (6): 332–9. doi:10.4149/bll_2016_066. PMID 27546365.
  8. ^ Pawar, Nisha R.; Buzza, Marguerite S.; Antalis, Toni M. (2019-01-15). "Membrane-Anchored Serine Proteases and Protease-Activated Receptor-2–Mediated Signaling: Co-Conspirators in Cancer Progression". Cancer Research. 79 (2): 301–310. doi:10.1158/0008-5472.CAN-18-1745. ISSN 0008-5472. PMC 6335149. PMID 30610085.
  9. ^ Bae, Jong-Sup; Rezaie, Alireza R. (2009). "Thrombin inhibits nuclear factor κB and RhoA pathways in cytokine-stimulated vascular endothelial cells when EPCR is occupied by protein C". Thrombosis and Haemostasis. 101 (03): 513–520. doi:10.1160/th08-09-0568. ISSN 0340-6245.

Further reading

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