title: Differential signaling by protease-activated receptors: implications for therapeutic targeting.
abstract: Protease-activated receptors (PARs) are a family of four G protein-coupled receptors that exhibit increasingly appreciated differences in signaling and regulation both within and between the receptor class. By nature of their proteolytic self-activation mechanism, PARs have unique processes of receptor activation, "ligand" binding, and desensitization/resensitization. These distinctive aspects have presented both challenges and opportunities in the targeting of PARs for therapeutic benefit-the most notable example of which is inhibition of PAR1 on platelets for the prevention of arterial thrombosis. However, more recent studies have uncovered further distinguishing features of PAR-mediated signaling, revealing mechanisms by which identical proteases elicit distinct effects in the same cell, as well as how distinct proteases produce different cellular consequences via the same receptor. Here we review this differential signaling by PARs, highlight how important distinctions between PAR1 and PAR4 are impacting on the progress of a new class of anti-thrombotic drugs, and discuss how these more recent insights into PAR signaling may present further opportunities for manipulating PAR activation and signaling in the development of novel therapies.
authors.affiliation: Australian Centre for Blood Diseases & Department of Clinical Haematology, Monash University, Melbourne 3004, Australia. tejminder.sidhu@monash.edu.
authors.forename: Tejminder S
authors.initials: TS
authors.lastname: Sidhu
authors.affiliation: Australian Centre for Blood Diseases & Department of Clinical Haematology, Monash University, Melbourne 3004, Australia. shauna.french@monash.edu.
authors.forename: Shauna L
authors.initials: SL
authors.lastname: French
authors.affiliation: Australian Centre for Blood Diseases & Department of Clinical Haematology, Monash University, Melbourne 3004, Australia. justin.hamilton@monash.edu.
authors.forename: Justin R
authors.initials: JR
authors.lastname: Hamilton
mesh_terms: D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D019281:Dimerization; D005343:Fibrinolytic Agents / Q000627:therapeutic use; D006801:Humans; D011486:Protein C / Q000378:metabolism; D044462:Receptors, Proteinase-Activated / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018179:Receptors, Thrombin / Q000037:antagonists & inhibitors / Q000378:metabolism; D018805:Sepsis / Q000628:therapy; D015398:Signal Transduction; D013927:Thrombosis / Q000517:prevention & control / Q000628:therapy
chemical_list: D005343:Fibrinolytic Agents; D011486:Protein C; D044462:Receptors, Proteinase-Activated; D018179:Receptors, Thrombin
references.citation: Nature. 1997 Sep 11;389(6647):183-6
references.pmid: 9296496
references.citation: Nature. 1998 Aug 13;394(6694):690-4
references.pmid: 9716134
references.citation: J Biol Chem. 2005 May 20;280(20):19808-14
references.pmid: 15769747
references.citation: Chest. 2003 Sep;124(3 Suppl):18S-25S
references.pmid: 12970120
references.citation: Proc Natl Acad Sci U S A. 2002 Nov 12;99(23):15072-7
references.pmid: 12397176
references.citation: Nat Med. 2002 Oct;8(10):1161-5
references.pmid: 12357249
references.citation: J Biol Chem. 2000 Aug 25;275(34):26333-42
references.pmid: 10831593
references.citation: J Biol Chem. 2000 Jun 30;275(26):19728-34
references.pmid: 10779527
references.citation: Blood. 2012 Dec 20;120(26):5237-46
references.pmid: 23149848
references.citation: J Clin Invest. 1999 Mar;103(6):879-87
references.pmid: 10079109
references.citation: Cell. 1991 Mar 22;64(6):1057-68
references.pmid: 1672265
references.citation: Pain. 2010 Nov;151(2):378-383
references.pmid: 20709455
references.citation: Mol Pharmacol. 2009 Oct;76(4):791-801
references.pmid: 19605524
references.citation: Blood. 2005 Apr 15;105(8):3178-84
references.pmid: 15626732
references.citation: Proc Natl Acad Sci U S A. 2011 Dec 13;108(50):19839-40
references.pmid: 22123954
references.citation: Cell Signal. 1996 Jan;8(1):59-66
references.pmid: 8777142
references.citation: Mol Pharmacol. 2013 Apr;83(4):781-92
references.pmid: 23307185
references.citation: J Biol Chem. 2012 Mar 23;287(13):10414-10423
references.pmid: 22318735
references.citation: Proc Natl Acad Sci U S A. 1994 Jan 18;91(2):504-8
references.pmid: 8290554
references.citation: Cell Signal. 2012 Jun;24(6):1351-60
references.pmid: 22306780
references.citation: Endocrinology. 1990 Feb;126(2):948-54
references.pmid: 2153536
references.citation: J Biol Chem. 2005 Apr 1;280(13):13122-8
references.pmid: 15665002
references.citation: Blood Cells Mol Dis. 2006 Mar-Apr;36(2):157-61
references.pmid: 16473534
references.citation: Proc Natl Acad Sci U S A. 2000 May 9;97(10):5255-60
references.pmid: 10805786
references.citation: J Biol Chem. 2000 Mar 10;275(10):6819-23
references.pmid: 10702240
references.citation: Cell Commun Signal. 2013 Nov 11;11:86
references.pmid: 24215724
references.citation: Curr Pharm Des. 2012;18(33):5197-214
references.pmid: 22724408
references.citation: Science. 2002 Jun 7;296(5574):1880-2
references.pmid: 12052963
references.citation: J Biol Chem. 1996 Jul 12;271(28):16466-71
references.pmid: 8663335
references.citation: Biochemistry. 1999 Apr 6;38(14):4572-85
references.pmid: 10194379
references.citation: Nature. 1991 Oct 17;353(6345):674-7
references.pmid: 1717851
references.citation: Blood. 2009 Mar 19;113(12):2859-66
references.pmid: 19141861
references.citation: Blood. 2006 May 15;107(10):3912-21
references.pmid: 16434493
references.citation: Mol Pharmacol. 2007 May;71(5):1399-406
references.pmid: 17303701
references.citation: Biol Chem. 2010 Jul;391(7):803-12
references.pmid: 20482314
references.citation: J Biol Chem. 2009 Jul 31;284(31):20638-48
references.pmid: 19439413
references.citation: Circulation. 2013 Jan 1;127(1):e6-e245
references.pmid: 23239837
references.citation: Stroke. 2013 Mar;44(3):691-8
references.pmid: 23396280
references.citation: PLoS One. 2013 Jun 11;8(6):e65528
references.pmid: 23776495
references.citation: Biochem J. 2005 Jun 15;388(Pt 3):967-72
references.pmid: 15537383
references.citation: Mol Biol Cell. 1998 Sep;9(9):2639-53
references.pmid: 9725917
references.citation: Proc Natl Acad Sci U S A. 2011 Dec 13;108(50):E1372-80
references.pmid: 22106258
references.citation: J Biol Chem. 2006 Jul 21;281(29):20077-84
references.pmid: 16709569
references.citation: J Biol Chem. 1992 Oct 15;267(29):20831-4
references.pmid: 1328213
references.citation: J Thromb Thrombolysis. 2013 Jan;35(1):1-9
references.pmid: 22644721
references.citation: J Neurosci. 2003 Jul 16;23(15):6176-80
references.pmid: 12867500
references.citation: J Biol Chem. 2000 Aug 18;275(33):25216-21
references.pmid: 10837487
references.citation: Nat Med. 2013 Dec;19(12):1609-16
references.pmid: 24216752
references.citation: Circulation. 2006 Mar 7;113(9):1244-54
references.pmid: 16505172
references.citation: Proc Natl Acad Sci U S A. 1994 Sep 27;91(20):9208-12
references.pmid: 7937743
references.citation: Proc Natl Acad Sci U S A. 1999 Sep 28;96(20):11189-93
references.pmid: 10500152
references.citation: N Engl J Med. 2012 Jan 5;366(1):20-33
references.pmid: 22077816
references.citation: Blood. 2008 Mar 1;111(5):2667-73
references.pmid: 18089851
references.citation: Nature. 2000 Sep 14;407(6801):258-64
references.pmid: 11001069
references.citation: J Biol Chem. 2000 May 5;275(18):13502-9
references.pmid: 10788464
references.citation: Trends Neurosci. 2011 Apr;34(4):198-209
references.pmid: 21353711
references.citation: J Biol Chem. 1997 Feb 14;272(7):4043-9
references.pmid: 9020112
references.citation: Pharmacol Rev. 2013 Sep 24;65(4):1198-213
references.pmid: 24064459
references.citation: Blood. 2012 Jan 19;119(3):874-83
references.pmid: 22117049
references.citation: Thromb Res. 2002 May 1;106(3):V275-84
references.pmid: 12356489
references.citation: Neuroscience. 2012 Dec 13;226:305-12
references.pmid: 23000623
references.citation: Mol Pharmacol. 2010 Jun;77(6):1005-15
references.pmid: 20215560
references.citation: Nat Immunol. 2007 Dec;8(12):1303-12
references.pmid: 17965715
references.citation: Blood Rev. 2009 Mar;23(2):61-5
references.pmid: 18644663
references.citation: J Endotoxin Res. 2003;9(5):317-21
references.pmid: 14577849
references.citation: J Thromb Haemost. 2005 Oct;3(10):2193-200
references.pmid: 16194198
references.citation: N Engl J Med. 2012 Apr 12;366(15):1404-13
references.pmid: 22443427
references.citation: Proc Natl Acad Sci U S A. 2007 Jan 2;104(1):288-92
references.pmid: 17190826
references.citation: Eur Heart J. 2010 Nov;31(21):2601-13
references.pmid: 20805115
references.citation: J Thromb Haemost. 2013 Jun;11 Suppl 1:242-53
references.pmid: 23809128
references.citation: Nature. 2000 Apr 6;404(6778):609-13
references.pmid: 10766244
references.citation: Blood. 2004 Feb 15;103(4):1342-7
references.pmid: 14576054
references.citation: Blood. 1998 Jun 1;91(11):4152-7
references.pmid: 9596661
references.citation: J Biol Chem. 1992 Jul 5;267(19):13146-9
references.pmid: 1320011
references.citation: Nature. 1997 Apr 3;386(6624):502-6
references.pmid: 9087410
references.citation: J Biol Chem. 2013 Nov 15;288(46):32979-90
references.pmid: 24052258
references.citation: Proc Natl Acad Sci U S A. 2007 Mar 27;104(13):5662-7
references.pmid: 17376866
references.citation: Blood. 2002 May 15;99(10):3629-36
references.pmid: 11986217
references.citation: J Neurosci. 2005 Apr 27;25(17):4319-29
references.pmid: 15858058