Introduction
Cleavage and activation of PARs and signal transduction
PAR activation by proteolytical cleavage
Protease | Major cleavage site | Additional cleavage sites | |
---|---|---|---|
Mammalian proteases | Thrombin | R41S42 | |
aPC | R46N47 | R41S42 | |
FVIIa | unknown | ||
FXa | R41S42 | ||
Trypsin | R41S42 | ||
Chymase | unknown | ||
MMP-1 | D39P40, L44L45, F87I88 | N47P48, R70L71,K82Q83 | |
MMP-2 | L38D39 | ||
MMP-3,-8,-9 | R41S42 | ||
MMP-12 | unknown | ||
MMP-13 | S42F43 | L38T39, mouse | |
Cathepsin G | R41S42, F55W56, Y69R70 | ||
Neutrophil elastase | A36T37, V72S73, A86F87 | ||
Proteinase-3 | A36T37, P48N49, V72S73, A92S93 | ||
Plasmin | K32A33, R41S42, R70 L71, K76 S77, K82 Q83 | ||
Kallikrein-4,-5,-6 | unknown | ||
Kallikrein-14 | R46N47 | ||
Granzyme A,B, K | unknown | ||
Calpain-1 | K32A33, S76K77 | ||
Non-mammalian proteases | PA-BJ | R41S42, R46N47 | |
Thrombocytin | R41S42, R46N47 | ||
DerP1 | unknown | ||
Gingipain R | R41S42 | ||
SpeB | L44L45 | ||
LepA | unknown | ||
S.pneumoniae proteases | unknown | ||
Thermolysin | F43L44, L44L45 | ||
penC | R41S42 |
Protease | Major cleavage site | Additional cleavage sites | |
---|---|---|---|
Mammalian proteases | Thrombin | R36S37 | |
aPC | unknown | ||
FXa | R36S37 | ||
Trypsin | R36S37 | K34G35, K51G52, K72L73 | |
Tryptase | R36S37 | ||
Chymase | G35R36 | L38I39, mouse | |
Matriptase | R36S37 | ||
Cathepsin G | F65S66 | F59S60, F64S65 | |
Cathepsin S | G40K41 | E56P57, mouse | |
Neutrophil elastase | A66S67, S67V68 | V42D43,V48T49,V53T54,V58T59,T74T75,V76F77 | |
Proteinase-3 | D62E63 | V48T49,V55E56,T57V58 V61D62,K72L73,T74T75,T75V76,V76F77 | |
Plasmin | R36S37 | K34G35 | |
Testisin | unknown | ||
Kallikrein-4, | unknown | ||
Kallikrein-5,-6,-14 | R36S37 | ||
Calpain-2 | unknown | ||
Non-mammalian proteases | Der-P1,-P2,-P3,-P9 | unknown | |
Cockroach E1-E3 | R36S37 | ||
Gingipain R | unknown | ||
LepA | unknown | ||
EPa | S37L38 | S38L39, rat | |
S.pneumoniae proteases | unknown | ||
Thermolysin | unknown | ||
Serralysin | unknown | ||
P.acnes proteases | unknown | ||
aPA | unknown | ||
Bromelain | unknown | ||
Ficin | unknown | ||
Papain | unknown | ||
penC | R36S37 |
Protease | Major cleavage site | Additional cleavage sites | |
---|---|---|---|
Mammalian proteases | Thrombin | K38T39 | mouse PAR3 at K37S38 |
aPC | R41G42 | ||
FXa | R41G42 | ||
Trypsin | unknown |
Protease | Major cleavage site | Additional cleavage sites | |
---|---|---|---|
Mammalian proteases | Thrombin | R47G48 | |
Trypsin | R47G48 | ||
Cathepsin G | R47G48 | ||
Kallikrein-14 | unknown | ||
Non-mammalian proteases | PA-BJ | R47G48 | |
Thrombocytin | R47G48 | ||
Der-P3 | unknown | ||
Gingipain R | R47G48 | ||
LepA | unknown | ||
S.pneumoniae proteases | unknown | ||
Bromelain | unknown | ||
Ficin | unknown | ||
Papain | unknown |
Mammalian proteases
Non-mammalian proteases
Cleavage-independent PAR activation by agonist peptides
PAR signaling
Activation pathways
Desensitization and termination
Role of PARs in inflammation
Systemic inflammation and inflammatory cells in the cardiovascular system
Chronic inflammation of the gastrointestinal tract
Inflammatory diseases of the respiratory system
Inflammatory skin diseases
Rheumatic disease
PAR modulators as targets for therapy
Class | Agonist/ Antagonist | Name | Receptor/Cell/Tissue type | Cellular response |
---|---|---|---|---|
Peptide | Agonist | SFLLRN/−NH2 | Human | |
TFLLRN/−NH2 | Human | |||
NPNDKYEPF/−NH2 | Human | |||
PRSFLLRN/−NH2 | Human | Induces platelet activation [86] | ||
Human | Induces ERK1/2 activation [280] | |||
Antagonist | YFLLRN | Human | ||
Peptidomimetic | Antagonist | RWJ-56110 | Human | |
Human | Blocks MMP-1 activaiton in SMCs [87] | |||
RWJ-58259 | Guinea pig | |||
Rat | Blocks thrombin induced calcium release in AoSMC Inhibits intimal thickening [111, 215, 264, 273] | |||
Mouse | ||||
Non-peptide small molecule | Antagonist | FR17113 | Human | |
Human | Inhibits thrombin and PAR1-AP induced ERK1/2 activation [287] | |||
ER129614–06 | Human | Blocks thrombin and PAR1-AP induced platelet activation [288] | ||
Guinea pig | Shows antithrombotic effects [289] | |||
F16357, F16618 | Human | Blocks PAR1-AP induced platelet activation [290] | ||
Rat | Shows antithrombotic effects [291] | |||
SCH79797 | Human | Blocks thrombin and PAR1-AP induced calcium release and platelet activation [292] | ||
Human, Mouse | Induces NETs formation and increases bacterial killing capacity [293] | |||
SCH203009 | Human | Blocks thrombin and PAR1-AP induced platelet activation [292] | ||
SCH530348 (vorapaxar) | Human, Monkey | Blocks thrombin and PAR1-AP induced platelet activation [266] | ||
E5555 (atopaxar) | Human | Blocks thrombin and PAR1-AP induced platelet activation and inhibits thrombus formation [267] | ||
Guinea pig | ||||
Q94 | Human | Blocks thrombin induced calcium release [295] | ||
Mouse | Blocks thrombin induced ERK1/2 activation [296] | |||
Pepducin | Antagonist | P1pal-12 | Human | Blocks thrombin induced platelet activation [268] |
Human | Blocks platelet activation [86] | |||
Human | Blocks MMP-1 induced endothelial damage [297] | |||
Mouse | ||||
P1-pal7 (PZ-128) | Human | Blocks MMP-1 induced Akt signaling in cancer cells [150] | ||
Human | Blocks platelet activation [86] | |||
Mouse | Inhibits tumor growth [280] | |||
Guinea pig | Prevents from systemic platelet activation [86] | |||
Parmodulin | Antagonist | ML161 (Parmodulin-2) | Human | Blocks thrombin and PAR1-AP induced platelet activation [299] |
Human | Blocks thrombin induced inflammatory signaling on endothelial cells [269] | |||
Mouse | Blocks thrombus formation [300] | |||
Antibiotic | Antagonist | Doxycycline | Human | |
Human | Blocks MMP-1 cleavage [303] | |||
Antibody | Antagonist | ATAP-2 WEDE | Human | Blocks thrombin cleavage of PAR1 and thrombin induced calcium release [147] |
Class | Agonist/ Antagonist | Name | Receptor/Cell/Tissue type | Cellular response |
---|---|---|---|---|
Peptide | Agonist | SLIGRL/−NH2 | Human, Rat | |
SLIGKV/−NH2 | Human | Induces calcium release [136] | ||
2f-LIGRLO/−NH2 | Human, Rat | Induces calcium release [140] | ||
Antagonist | FSLLRY-NH2 | Human | Blocks trypsin, not SLIGRL activation, reduces proinflammatory IL-8 and TNFα [82] | |
Rat | Inhibits neuropathic pain [304] | |||
LSIGRL-NH2 | Human | Blocks trypsin, not SLIGRL induced calcium release [305] | ||
Peptidomimetic | Antagonist | K14585, K12940 | Human | Reduces SLIGKV induced calcium release [306] |
Human | Inhibits SLIGRL induced NFkB activation [307] | |||
C391a | Human, Mouse | Blocks calcium release and MAPK activation [308] | ||
Non-peptide small molecule | Agonist | GB110 | Human | Induces calcium release [309] |
AC-5541, AC-264613 | Human | Induces calcium release [310] | ||
Rat | Induces edema and hyperalgesia [310] | |||
Antagonist | ENMD-1068 | Human | Blocks p.acnes induced calcium release and induction of IL-1a, IL-8 and TNFα [92] | |
Human | Inhibited FVIIa induced cancer cell migration [311] | |||
Mouse | Reduces joint inflammation [260] | |||
Mouse | Blocks calcium release and reduces liver fibrosis [312] | |||
GB83 | Human | Inhibits trypsin and PAR2-AP calcium release [313] | ||
GB88 | Human | Blocks PAR2 induced calcium release [309] | ||
Rat | ||||
AZ8838 AZ3451 | Human | Blocks PAR2-AP induced calcium release and β-arrestin recruitment [315] | ||
Pepducin | Antagonist | P2pal-18S | Human | Blocks PAR2 induced calcium release [316] |
Mouse | Decreases risk for developing severe biliary pancreatitis [317] | |||
P2pal-14GQ | Human | Blocks PAR2 induced calcium release [316] | ||
Antibiotic | Antagonist | Tetracyclines (Tetracycline, Doxycycline, Minocycline) | Human | Inhibits SLIGRL induced IL-8 release [318] |
Mouse | Topical application of tetracycline decreases PAR2 induced skin inflammation [319] | |||
Rat | Subantimicrobial doses of doxycycline inhibit PAR2 induced inflammation [320] | |||
Antibody | SAM-11 | Mouse | Reduces joint inflammation [260] | |
Mouse | Prevents allergic inflammation [124] | |||
B5 | Mouse | Reduces joint inflammation [260] | ||
Mouse | Inhibits allergic airway inflammation [124] | |||
MAB3949 | Human | Blocks trypsin induced PAR2 activation [315] |
Class | Agonist/ Antagonist | Name | Receptor/Cell/Tissue type | Cellular response |
---|---|---|---|---|
Peptide | Agonist | GYPGQV/−NH2 | Human, Rat | Induces platelet activation [144] |
GYPGKF/−NH2 | Human, Rat | Induces platelet activation [144] | ||
AYPGKF/−NH2 | Human, Mouse | Induces platelet activation [145] | ||
Peptidomimetic | Antagonist | tc-YGPKF | Rat | Blocks thrombin and PAR4-AP induced platelets aggregation [321] |
Non-peptide small molecule | Antagonist | YD-3 | Human | |
Mouse, Rat, Rabbit | ||||
ML-354 | Human | |||
BMS-986120 | Human | Blocks PAR4-AP induced calcium release and platelet activation [329] | ||
Human | Blocks thrombus formation at high shear stress [277] | |||
Monkey | Blocks platelet activation [329] | |||
Pepducin | Antagonist | P4pal-10 | Human, Mouse | Blocks thrombin and PAR4-AP induced platelet activation [268] |
Rat | Blocks thrombin and PAR4-AP induced platelets activation [330] | |||
P4pal-i1 | Human | Blocks PAR4 induced platelets activation [150] |