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Potent and selective [[small molecule]] [[agonist]]s and [[receptor antagonist|antagonists]] for PAR2 have been discovered.<ref name="pmid18768780">{{cite journal | vauthors = Gardell LR, Ma JN, Seitzberg JG, Knapp AE, Schiffer HH, Tabatabaei A, Davis CN, Owens M, Clemons B, Wong KK, Lund B, Nash NR, Gao Y, Lameh J, Schmelzer K, Olsson R, Burstein ES | title = Identification and characterization of novel small-molecule protease-activated receptor 2 agonists | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 327 | issue = 3 | pages = 799–808 | date = December 2008 | pmid = 18768780 | doi = 10.1124/jpet.108.142570 }}</ref><ref name="pmid20873792">{{cite journal | vauthors = Barry GD, Suen JY, Le GT, Cotterell A, Reid RC, Fairlie DP | title = Novel agonists and antagonists for human protease activated receptor 2 | journal = Journal of Medicinal Chemistry | volume = 53 | issue = 20 | pages = 7428–40 | date = October 2010 | pmid = 20873792 | doi = 10.1021/jm100984y }}</ref><ref>{{cite journal | vauthors = Yau MK, Liu L, Suen JY, Lim J, Lohman RJ, Jiang Y, Cotterell AJ, Barry GD, Mak JY, Vesey DA, Reid RC, Fairlie DP | title = PAR2 Modulators Derived from GB88 | journal = ACS Medicinal Chemistry Letters | volume = 7 | issue = 12 | pages = 1179–1184 | date = December 2016 | pmid = 27994760 | pmc = 5150695 | doi = 10.1021/acsmedchemlett.6b00306 }}</ref>
Potent and selective [[small molecule]] [[agonist]]s and [[receptor antagonist|antagonists]] for PAR2 have been discovered.<ref name="pmid18768780">{{cite journal | vauthors = Gardell LR, Ma JN, Seitzberg JG, Knapp AE, Schiffer HH, Tabatabaei A, Davis CN, Owens M, Clemons B, Wong KK, Lund B, Nash NR, Gao Y, Lameh J, Schmelzer K, Olsson R, Burstein ES | title = Identification and characterization of novel small-molecule protease-activated receptor 2 agonists | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 327 | issue = 3 | pages = 799–808 | date = December 2008 | pmid = 18768780 | doi = 10.1124/jpet.108.142570 }}</ref><ref name="pmid20873792">{{cite journal | vauthors = Barry GD, Suen JY, Le GT, Cotterell A, Reid RC, Fairlie DP | title = Novel agonists and antagonists for human protease activated receptor 2 | journal = Journal of Medicinal Chemistry | volume = 53 | issue = 20 | pages = 7428–40 | date = October 2010 | pmid = 20873792 | doi = 10.1021/jm100984y }}</ref><ref>{{cite journal | vauthors = Yau MK, Liu L, Suen JY, Lim J, Lohman RJ, Jiang Y, Cotterell AJ, Barry GD, Mak JY, Vesey DA, Reid RC, Fairlie DP | title = PAR2 Modulators Derived from GB88 | journal = ACS Medicinal Chemistry Letters | volume = 7 | issue = 12 | pages = 1179–1184 | date = December 2016 | pmid = 27994760 | pmc = 5150695 | doi = 10.1021/acsmedchemlett.6b00306 }}</ref>

[[Functional selectivity]] occurs with PAR2, several proteases cleave PAR2 at distinct sites leading to biased signalling<ref>{{Cite journal|last=Zhao|first=Peishen|last2=Metcalf|first2=Matthew|last3=Bunnett|first3=Nigel W.|date=2014|title=Biased Signaling of Protease-Activated Receptors|url=https://www.frontiersin.org/articles/10.3389/fendo.2014.00067/full|journal=Frontiers in Endocrinology|language=English|volume=5|doi=10.3389/fendo.2014.00067|issn=1664-2392|pmc=PMC4026716|pmid=24860547}}</ref>. Synthetic small ligands also modulate biased signalling leading to different functional responses.<ref>{{Cite journal|last=Jiang|first=Yuhong|last2=Yau|first2=Mei-Kwan|last3=Kok|first3=W. Mei|last4=Lim|first4=Junxian|last5=Wu|first5=Kai-Chen|last6=Liu|first6=Ligong|last7=Hill|first7=Timothy A.|last8=Suen|first8=Jacky Y.|last9=Fairlie|first9=David P.|date=2017-03-14|title=Biased Signaling by Agonists of Protease Activated Receptor 2|url=https://pubs.acs.org/doi/10.1021/acschembio.6b01088|journal=ACS Chemical Biology|language=EN|volume=12|issue=5|pages=1217–1226|doi=10.1021/acschembio.6b01088|issn=1554-8929}}</ref>


== See also ==
== See also ==

Revision as of 23:08, 14 September 2018

F2RL1
Identifiers
AliasesF2RL1, GPR11, PAR2, Protease activated receptor 2, F2R like trypsin receptor 1
External IDsOMIM: 600933; MGI: 101910; HomoloGene: 21087; GeneCards: F2RL1; OMA:F2RL1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

2150

14063

Ensembl

ENSG00000164251

ENSMUSG00000021678

UniProt

P55085

P55086

RefSeq (mRNA)

NM_005242

NM_007974

RefSeq (protein)

NP_005233

NP_032000

Location (UCSC)Chr 5: 76.82 – 76.84 MbChr 13: 95.65 – 95.66 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Protease activated receptor 2 (PAR2) also known as coagulation factor II (thrombin) receptor-like 1 (F2RL1) or G-protein coupled receptor 11 (GPR11) is a protein that in humans is encoded by the F2RL1 gene. PAR2 modulates inflammatory responses, obesity,[5] metabolism,[6] and acts as a sensor for proteolytic enzymes generated during infection.[7]

Gene

The F2RL1 gene contains two exons and is widely expressed in human tissues. The predicted protein sequence is 83% identical to the mouse receptor sequence.[8]

Mechanism of activation

PAR2 is a member of the large family of 7-transmembrane receptors that couple to guanosine-nucleotide-binding proteins. PAR2 is also a member of the protease-activated receptor family. It is activated by trypsin, but not by thrombin. It is activated by proteolytic cleavage of its extracellular amino terminus. The new amino terminus functions as a tethered ligand and activates the receptor. Additionally, these receptors can be activated by exogenous proteases, such as house dust mite protein Der P9.[9] These receptors can also be activated non-protealytically, by exogenous peptide sequences that mimic the final amino acids of the tethered ligand.[10]

Agonists and antagonists

Potent and selective small molecule agonists and antagonists for PAR2 have been discovered.[11][12][13]

Functional selectivity occurs with PAR2, several proteases cleave PAR2 at distinct sites leading to biased signalling[14]. Synthetic small ligands also modulate biased signalling leading to different functional responses.[15]

See also

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000164251 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000021678 – 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. ^ Lim J, Iyer A, Liu L, Suen JY, Lohman RJ, Seow V, Yau MK, Brown L, Fairlie DP (December 2013). "Diet-induced obesity, adipose inflammation, and metabolic dysfunction correlating with PAR2 expression are attenuated by PAR2 antagonism". FASEB Journal. 27 (12): 4757–67. doi:10.1096/fj.13-232702. PMID 23964081.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  6. ^ Badeanlou L, Furlan-Freguia C, Yang G, Ruf W, Samad F (October 2011). "Tissue factor-protease-activated receptor 2 signaling promotes diet-induced obesity and adipose inflammation". Nature Medicine. 17 (11): 1490–7. doi:10.1038/nm.2461. PMC 3210891. PMID 22019885.
  7. ^ Lee SE, Jeong SK, Lee SH (November 2010). "Protease and protease-activated receptor-2 signaling in the pathogenesis of atopic dermatitis". Yonsei Medical Journal. 51 (6): 808–22. doi:10.3349/ymj.2010.51.6.808. PMC 2995962. PMID 20879045.
  8. ^ "Entrez Gene: F2RL1 coagulation factor II (thrombin) receptor-like 1".
  9. ^ Sun G, Stacey MA, Schmidt M, Mori L, Mattoli S (July 2001). "Interaction of mite allergens Der p3 and Der p9 with protease-activated receptor-2 expressed by lung epithelial cells". Journal of Immunology. 167 (2): 1014–21. doi:10.4049/jimmunol.167.2.1014. PMID 11441110.
  10. ^ Kawabata A, Kanke T, Yonezawa D, Ishiki T, Saka M, Kabeya M, Sekiguchi F, Kubo S, Kuroda R, Iwaki M, Katsura K, Plevin R (June 2004). "Potent and metabolically stable agonists for protease-activated receptor-2: evaluation of activity in multiple assay systems in vitro and in vivo". The Journal of Pharmacology and Experimental Therapeutics. 309 (3): 1098–107. doi:10.1124/jpet.103.061010. PMID 14976227.
  11. ^ Gardell LR, Ma JN, Seitzberg JG, Knapp AE, Schiffer HH, Tabatabaei A, Davis CN, Owens M, Clemons B, Wong KK, Lund B, Nash NR, Gao Y, Lameh J, Schmelzer K, Olsson R, Burstein ES (December 2008). "Identification and characterization of novel small-molecule protease-activated receptor 2 agonists". The Journal of Pharmacology and Experimental Therapeutics. 327 (3): 799–808. doi:10.1124/jpet.108.142570. PMID 18768780.
  12. ^ Barry GD, Suen JY, Le GT, Cotterell A, Reid RC, Fairlie DP (October 2010). "Novel agonists and antagonists for human protease activated receptor 2". Journal of Medicinal Chemistry. 53 (20): 7428–40. doi:10.1021/jm100984y. PMID 20873792.
  13. ^ Yau MK, Liu L, Suen JY, Lim J, Lohman RJ, Jiang Y, Cotterell AJ, Barry GD, Mak JY, Vesey DA, Reid RC, Fairlie DP (December 2016). "PAR2 Modulators Derived from GB88". ACS Medicinal Chemistry Letters. 7 (12): 1179–1184. doi:10.1021/acsmedchemlett.6b00306. PMC 5150695. PMID 27994760.
  14. ^ Zhao, Peishen; Metcalf, Matthew; Bunnett, Nigel W. (2014). "Biased Signaling of Protease-Activated Receptors". Frontiers in Endocrinology. 5. doi:10.3389/fendo.2014.00067. ISSN 1664-2392. PMC 4026716. PMID 24860547.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)
  15. ^ Jiang, Yuhong; Yau, Mei-Kwan; Kok, W. Mei; Lim, Junxian; Wu, Kai-Chen; Liu, Ligong; Hill, Timothy A.; Suen, Jacky Y.; Fairlie, David P. (2017-03-14). "Biased Signaling by Agonists of Protease Activated Receptor 2". ACS Chemical Biology. 12 (5): 1217–1226. doi:10.1021/acschembio.6b01088. ISSN 1554-8929.

Further reading

External links

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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