Protease-activated receptor 2: Difference between revisions
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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 | vauthors = Zhao P, Metcalf M, Bunnett NW | title = Biased signaling of protease-activated receptors | journal = Frontiers in Endocrinology | volume = 5 | pages = 67 | date = 2014 | pmid = 24860547 | pmc = 4026716 | doi = 10.3389/fendo.2014.00067 }}</ref> Synthetic small ligands also modulate biased signalling leading to different functional responses.<ref>{{cite journal | vauthors = Jiang Y, Yau MK, Kok WM, Lim J, Wu KC, Liu L, Hill TA, Suen JY, Fairlie DP | title = Biased Signaling by Agonists of Protease Activated Receptor 2 | journal = ACS Chemical Biology | volume = 12 | issue = 5 | pages = 1217–1226 | date = May 2017 | pmid = 28169521 | doi = 10.1021/acschembio.6b01088 }}</ref> | |||
So far, PAR2 has been co-crystallized with two different antagonist ligands,<ref>{{cite journal | vauthors = Cheng RK, Fiez-Vandal C, Schlenker O, Edman K, Aggeler B, Brown DG, Brown GA, Cooke RM, Dumelin CE, Doré AS, Geschwindner S, Grebner C, Hermansson NO, Jazayeri A, Johansson P, Leong L, Prihandoko R, Rappas M, Soutter H, Snijder A, Sundström L, Tehan B, Thornton P, Troast D, Wiggin G, Zhukov A, Marshall FH, Dekker N | title = Structural insight into allosteric modulation of protease-activated receptor 2 | journal = Nature | volume = 545 | issue = 7652 | pages = 112–115 | date = May 2017 | pmid = 28445455 | doi = 10.1038/nature22309 }}</ref> while an agonist-bound state model of PAR2 (with the endogenous ligand SLIGKV) has been determined through [[Mutagenesis (molecular biology technique)|mutagenesis]] and [[structure-based drug design]].<ref>{{Cite journal | vauthors = Kennedy AJ, Ballante F, Johansson JR, Milligan G, Sundström L, Nordqvist A, Carlsson J |date=2018-10-16 |title=Structural Characterization of Agonist Binding to Protease-Activated Receptor 2 through Mutagenesis and Computational Modeling |journal=ACS Pharmacology & Translational Science |doi=10.1021/acsptsci.8b00019}}</ref> | |||
== See also == | == See also == | ||
*[[Protease-activated receptor]] | *[[Protease-activated receptor]] | ||
== References == | == References == | ||
{{reflist| | {{reflist|32em}} | ||
{{Clear}} | {{Clear}} | ||
== Further reading == | == Further reading == | ||
{{refbegin| | {{refbegin|32em}} | ||
* {{cite journal | vauthors = Kunzelmann K, Schreiber R, König J, Mall M | title = Ion transport induced by proteinase-activated receptors (PAR2) in colon and airways | journal = Cell Biochemistry and Biophysics | volume = 36 | issue = 2-3 | pages = 209–14 | year = 2003 | pmid = 12139406 | doi = 10.1385/CBB:36:2-3:209 }} | * {{cite journal | vauthors = Kunzelmann K, Schreiber R, König J, Mall M | title = Ion transport induced by proteinase-activated receptors (PAR2) in colon and airways | journal = [[Cell Biochemistry and Biophysics]] | volume = 36 | issue = 2-3 | pages = 209–14 | year = 2003 | pmid = 12139406 | doi = 10.1385/CBB:36:2-3:209 }} | ||
* {{cite journal | vauthors = Kawabata A | title = PAR-2: structure, function and relevance to human diseases of the gastric mucosa | journal = Expert Reviews in Molecular Medicine | volume = 4 | issue = 16 | pages = 1–17 | date = July 2002 | pmid = 14585156 | doi = 10.1017/S1462399402004799 }} | * {{cite journal | vauthors = Kawabata A | title = PAR-2: structure, function and relevance to human diseases of the gastric mucosa | journal = Expert Reviews in Molecular Medicine | volume = 4 | issue = 16 | pages = 1–17 | date = July 2002 | pmid = 14585156 | doi = 10.1017/S1462399402004799 }} | ||
* {{cite journal | vauthors = Bushell T | title = The emergence of proteinase-activated receptor-2 as a novel target for the treatment of inflammation-related CNS disorders | journal = The Journal of Physiology | volume = 581 | issue = Pt 1 | pages = 7–16 | date = May 2007 | pmid = 17347265 | pmc = 2075212 | doi = 10.1113/jphysiol.2007.129577 }} | * {{cite journal | vauthors = Bushell T | title = The emergence of proteinase-activated receptor-2 as a novel target for the treatment of inflammation-related CNS disorders | journal = The Journal of Physiology | volume = 581 | issue = Pt 1 | pages = 7–16 | date = May 2007 | pmid = 17347265 | pmc = 2075212 | doi = 10.1113/jphysiol.2007.129577 }} | ||
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[[Category:Receptors]] | [[Category:Receptors]] | ||
[[Category:G protein coupled receptors]] | [[Category:G protein-coupled receptors]] | ||
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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,[1] metabolism,[2] and acts as a sensor for proteolytic enzymes generated during infection.[3]
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.[4]
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.[5] These receptors can also be activated non-protealytically, by exogenous peptide sequences that mimic the final amino acids of the tethered ligand.[6]
Agonists and antagonists
Potent and selective small molecule agonists and antagonists for PAR2 have been discovered.[7][8][9]
Functional selectivity occurs with PAR2, several proteases cleave PAR2 at distinct sites leading to biased signalling.[10] Synthetic small ligands also modulate biased signalling leading to different functional responses.[11]
So far, PAR2 has been co-crystallized with two different antagonist ligands,[12] while an agonist-bound state model of PAR2 (with the endogenous ligand SLIGKV) has been determined through mutagenesis and structure-based drug design.[13]
See also
References
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ "Entrez Gene: F2RL1 coagulation factor II (thrombin) receptor-like 1".
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ Zhao P, Metcalf M, Bunnett NW (2014). "Biased signaling of protease-activated receptors". Frontiers in Endocrinology. 5: 67. doi:10.3389/fendo.2014.00067. PMC 4026716. PMID 24860547.
- ↑ Jiang Y, Yau MK, Kok WM, Lim J, Wu KC, Liu L, Hill TA, Suen JY, Fairlie DP (May 2017). "Biased Signaling by Agonists of Protease Activated Receptor 2". ACS Chemical Biology. 12 (5): 1217–1226. doi:10.1021/acschembio.6b01088. PMID 28169521.
- ↑ Cheng RK, Fiez-Vandal C, Schlenker O, Edman K, Aggeler B, Brown DG, Brown GA, Cooke RM, Dumelin CE, Doré AS, Geschwindner S, Grebner C, Hermansson NO, Jazayeri A, Johansson P, Leong L, Prihandoko R, Rappas M, Soutter H, Snijder A, Sundström L, Tehan B, Thornton P, Troast D, Wiggin G, Zhukov A, Marshall FH, Dekker N (May 2017). "Structural insight into allosteric modulation of protease-activated receptor 2". Nature. 545 (7652): 112–115. doi:10.1038/nature22309. PMID 28445455.
- ↑ Kennedy AJ, Ballante F, Johansson JR, Milligan G, Sundström L, Nordqvist A, Carlsson J (2018-10-16). "Structural Characterization of Agonist Binding to Protease-Activated Receptor 2 through Mutagenesis and Computational Modeling". ACS Pharmacology & Translational Science. doi:10.1021/acsptsci.8b00019.
Further reading
- Kunzelmann K, Schreiber R, König J, Mall M (2003). "Ion transport induced by proteinase-activated receptors (PAR2) in colon and airways". Cell Biochemistry and Biophysics. 36 (2–3): 209–14. doi:10.1385/CBB:36:2-3:209. PMID 12139406.
- Kawabata A (July 2002). "PAR-2: structure, function and relevance to human diseases of the gastric mucosa". Expert Reviews in Molecular Medicine. 4 (16): 1–17. doi:10.1017/S1462399402004799. PMID 14585156.
- Bushell T (May 2007). "The emergence of proteinase-activated receptor-2 as a novel target for the treatment of inflammation-related CNS disorders". The Journal of Physiology. 581 (Pt 1): 7–16. doi:10.1113/jphysiol.2007.129577. PMC 2075212. PMID 17347265.
- Nystedt S, Emilsson K, Larsson AK, Strömbeck B, Sundelin J (August 1995). "Molecular cloning and functional expression of the gene encoding the human proteinase-activated receptor 2". European Journal of Biochemistry. 232 (1): 84–9. doi:10.1111/j.1432-1033.1995.tb20784.x. PMID 7556175.
- Santulli RJ, Derian CK, Darrow AL, Tomko KA, Eckardt AJ, Seiberg M, Scarborough RM, Andrade-Gordon P (September 1995). "Evidence for the presence of a protease-activated receptor distinct from the thrombin receptor in human keratinocytes". Proceedings of the National Academy of Sciences of the United States of America. 92 (20): 9151–5. doi:10.1073/pnas.92.20.9151. PMC 40942. PMID 7568091.
- Nystedt S, Emilsson K, Wahlestedt C, Sundelin J (September 1994). "Molecular cloning of a potential proteinase activated receptor". Proceedings of the National Academy of Sciences of the United States of America. 91 (20): 9208–12. doi:10.1073/pnas.91.20.9208. PMC 44781. PMID 7937743.
- Mirza H, Yatsula V, Bahou WF (April 1996). "The proteinase activated receptor-2 (PAR-2) mediates mitogenic responses in human vascular endothelial cells". The Journal of Clinical Investigation. 97 (7): 1705–14. doi:10.1172/JCI118597. PMC 507235. PMID 8601636.
- Bohm SK, Kong W, Bromme D, Smeekens SP, Anderson DC, Connolly A, Kahn M, Nelken NA, Coughlin SR, Payan DG, Bunnett NW (March 1996). "Molecular cloning, expression and potential functions of the human proteinase-activated receptor-2". The Biochemical Journal. 314 ( Pt 3) (3): 1009–16. PMC 1217107. PMID 8615752.
- Böhm SK, Khitin LM, Grady EF, Aponte G, Payan DG, Bunnett NW (September 1996). "Mechanisms of desensitization and resensitization of proteinase-activated receptor-2". The Journal of Biological Chemistry. 271 (36): 22003–16. doi:10.1074/jbc.271.36.22003. PMID 8703006.
- Kahn M, Ishii K, Kuo WL, Piper M, Connolly A, Shi YP, Wu R, Lin CC, Coughlin SR (May 1996). "Conserved structure and adjacent location of the thrombin receptor and protease-activated receptor 2 genes define a protease-activated receptor gene cluster". Molecular Medicine. 2 (3): 349–57. PMC 2230143. PMID 8784787.
- Molino M, Barnathan ES, Numerof R, Clark J, Dreyer M, Cumashi A, Hoxie JA, Schechter N, Woolkalis M, Brass LF (February 1997). "Interactions of mast cell tryptase with thrombin receptors and PAR-2". The Journal of Biological Chemistry. 272 (7): 4043–9. doi:10.1074/jbc.272.7.4043. PMID 9020112.
- Howells GL, Macey MG, Chinni C, Hou L, Fox MT, Harriott P, Stone SR (April 1997). "Proteinase-activated receptor-2: expression by human neutrophils". Journal of Cell Science. 110 ( Pt 7) (7): 881–7. PMID 9133675.
- D'Andrea MR, Derian CK, Leturcq D, Baker SM, Brunmark A, Ling P, Darrow AL, Santulli RJ, Brass LF, Andrade-Gordon P (February 1998). "Characterization of protease-activated receptor-2 immunoreactivity in normal human tissues". The Journal of Histochemistry and Cytochemistry. 46 (2): 157–64. doi:10.1177/002215549804600204. PMID 9446822.
- Guyonnet Dupérat V, Jacquelin B, Boisseau P, Arveiler B, Nurden AT (July 1998). "Protease-activated receptor genes are clustered on 5q13". Blood. 92 (1): 25–31. PMID 9639495.
- Steinhoff M, Corvera CU, Thoma MS, Kong W, McAlpine BE, Caughey GH, Ansel JC, Bunnett NW (August 1999). "Proteinase-activated receptor-2 in human skin: tissue distribution and activation of keratinocytes by mast cell tryptase". Experimental Dermatology. 8 (4): 282–94. doi:10.1111/j.1600-0625.1999.tb00383.x. PMID 10439226.
- Takeuchi T, Harris JL, Huang W, Yan KW, Coughlin SR, Craik CS (August 2000). "Cellular localization of membrane-type serine protease 1 and identification of protease-activated receptor-2 and single-chain urokinase-type plasminogen activator as substrates". The Journal of Biological Chemistry. 275 (34): 26333–42. doi:10.1074/jbc.M002941200. PMID 10831593.
- Loew D, Perrault C, Morales M, Moog S, Ravanat C, Schuhler S, Arcone R, Pietropaolo C, Cazenave JP, van Dorsselaer A, Lanza F (September 2000). "Proteolysis of the exodomain of recombinant protease-activated receptors: prediction of receptor activation or inactivation by MALDI mass spectrometry". Biochemistry. 39 (35): 10812–22. doi:10.1021/bi0003341. PMID 10978167.
- Knight DA, Lim S, Scaffidi AK, Roche N, Chung KF, Stewart GA, Thompson PJ (November 2001). "Protease-activated receptors in human airways: upregulation of PAR-2 in respiratory epithelium from patients with asthma". The Journal of Allergy and Clinical Immunology. 108 (5): 797–803. doi:10.1067/mai.2001.119025. PMID 11692107.
- Miike S, McWilliam AS, Kita H (December 2001). "Trypsin induces activation and inflammatory mediator release from human eosinophils through protease-activated receptor-2". Journal of Immunology. 167 (11): 6615–22. doi:10.4049/jimmunol.167.11.6615. PMID 11714832.
- Asokananthan N, Graham PT, Fink J, Knight DA, Bakker AJ, McWilliam AS, Thompson PJ, Stewart GA (April 2002). "Activation of protease-activated receptor (PAR)-1, PAR-2, and PAR-4 stimulates IL-6, IL-8, and prostaglandin E2 release from human respiratory epithelial cells". Journal of Immunology. 168 (7): 3577–85. doi:10.4049/jimmunol.168.7.3577. PMID 11907122.
- Wong DM, Tam V, Lam R, Walsh KA, Tatarczuch L, Pagel CN, Reynolds EC, O'Brien-Simpson NM, Mackie EJ, Pike RN (February 2010). "Protease-activated receptor 2 has pivotal roles in cellular mechanisms involved in experimental periodontitis". Infection and Immunity. 78 (2): 629–38. doi:10.1128/IAI.01019-09. PMC 2812191. PMID 19933835.
External links
- "Protease-Activated Receptors: PAR2". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.