The role of PAR4 in thrombin-induced thromboxane production in human platelets.
There are two protease-activated receptors (PARs), PAR1 and PAR4, in human platelets. It has been suggested that PAR1 mediates platelet responses to low concentrations of thrombin, whereas PAR4 mediates signaling only at high concentrations. In the present study, we used a selective PAR4 blocker, YD-3, to investigate the role of PAR4 in thrombin-induced thromboxane formation in human platelets. YD-3 completely prevented thromboxane production by either a low concentration of thrombin (0.1 U/ml) or the PAR4 agonist peptide GYPGKF. In contrast, YD-3 did not affect thromboxane production caused by the PAR1 agonist peptide SFLLRN, collagen or arachidonic acid. YD-3 also decreased [(3) H]arachidonic acid release from thrombin-stimulated platelets. Moreover, desensitization of platelets with GYPGKF prevented low thrombin-induced thromboxane formation. The decreased thromboxane production by YD-3 is linked to inhibition of calcium influx in thrombin-stimulated platelets. These results suggest that PAR4 plays an important role in the regulation of thromboxane formation in platelets responding to thrombin through prolonged elevation of [Ca(2+)](i) and activation of phospholipase A(2). These data also indicate that PAR4 can be activated by relatively low concentrations of thrombin in human platelets. The selective inhibition of thrombin-induced thromboxane production by YD-3 may be of therapeutic benefit for thrombotic diseases.
Wu
Chin-Chung
CC
Graduate Institute of Natural Products, Kaohsiung Medical University, Taiwan.
Hwang
Tsong-Long
TL
Liao
Chang-Hui
CH
Kuo
Sheng-Chu
SC
Lee
Fang-Yu
FY
Teng
Che-Ming
CM
D016718:Arachidonic Acid / Q000378:metabolism; D001792:Blood Platelets / Q000378:metabolism*; D006801:Humans; D007191:Indazoles / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects / Q000502:physiology; D018179:Receptors, Thrombin / Q000819:agonists / Q000502:physiology*; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology*; D013931:Thromboxanes / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors
C412964:1-benzyl-3-(ethoxycarbonylpheny)-indazole; D007191:Indazoles; C435606:RWJ-56110; D018179:Receptors, Thrombin; D013931:Thromboxanes; D016718:Arachidonic Acid; D014508:Urea; D013917:Thrombin; C112908:protease-activated receptor 4; D010975:Platelet Aggregation Inhibitors