PMID- 10079109
OWN - NLM
STAT- MEDLINE
DCOM- 19990402
LR  - 20181201
IS  - 0021-9738 (Print)
IS  - 0021-9738 (Linking)
VI  - 103
IP  - 6
DP  - 1999 Mar
TI  - Protease-activated receptors 1 and 4 mediate activation of human platelets by
      thrombin.
PG  - 879-87
AB  - Because of the role of thrombin and platelets in myocardial infarction and other 
      pathological processes, identifying and blocking the receptors by which thrombin 
      activates platelets has been an important goal. Three protease-activated
      receptors (PARs) for thrombin -- PAR1, PAR3, and PAR4 -- are now known. PAR1
      functions in human platelets, and the recent observation that a PAR4-activating
      peptide activates human platelets suggests that PAR4 also acts in these cells.
      Whether PAR1 and PAR4 account for activation of human platelets by thrombin, or
      whether PAR3 or still other receptors contribute, is unknown. We have examined
      the roles of PAR1, PAR3, and PAR4 in platelets. PAR1 and PAR4 mRNA and protein
      were detected in human platelets. Activation of either receptor was sufficient to
      trigger platelet secretion and aggregation. Inhibition of PAR1 alone by
      antagonist, blocking antibody, or desensitization blocked platelet activation by 
      1 nM thrombin but only modestly attenuated platelet activation by 30 nM thrombin.
      Inhibition of PAR4 alone using a blocking antibody had little effect at either
      thrombin concentration. Strikingly, simultaneous inhibition of both PAR1 and PAR4
      virtually ablated platelet secretion and aggregation, even at 30 nM thrombin.
      These observations suggest that PAR1 and PAR4 account for most, if not all,
      thrombin signaling in platelets and that antagonists that block these receptors
      might be useful antithrombotic agents.
FAU - Kahn, M L
AU  - Kahn ML
AD  - Cardiovascular Research Institute and Daiichi Research Center, University of
      California-San Francisco, San Francisco, California 94143-0130, USA.
FAU - Nakanishi-Matsui, M
AU  - Nakanishi-Matsui M
FAU - Shapiro, M J
AU  - Shapiro MJ
FAU - Ishihara, H
AU  - Ishihara H
FAU - Coughlin, S R
AU  - Coughlin SR
LA  - eng
GR  - R01 HL044907/HL/NHLBI NIH HHS/United States
GR  - K08 HL-03731/HL/NHLBI NIH HHS/United States
GR  - HL-44907/HL/NHLBI NIH HHS/United States
GR  - R01 HL059202/HL/NHLBI NIH HHS/United States
GR  - HL-59202/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Clin Invest
JT  - The Journal of clinical investigation
JID - 7802877
RN  - 0 (RNA, Messenger)
RN  - 0 (Receptor, PAR-1)
RN  - 0 (Receptor, PAR-2)
RN  - 0 (Receptors, Thrombin)
RN  - 0 (protease-activated receptor 3)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
RN  - EC 3.4.21.5 (Thrombin)
SB  - AIM
SB  - IM
MH  - Adenosine Triphosphate/metabolism
MH  - Cells, Cultured
MH  - Humans
MH  - Leukocytes, Mononuclear/cytology
MH  - Megakaryocytes/cytology
MH  - Neutrophils/cytology
MH  - *Platelet Activation
MH  - Platelet Aggregation
MH  - RNA, Messenger/analysis
MH  - Receptor, PAR-1
MH  - Receptor, PAR-2
MH  - Receptors, Thrombin/agonists/antagonists & inhibitors/genetics/*metabolism
MH  - Signal Transduction
MH  - Species Specificity
MH  - Thrombin/*pharmacology
PMC - PMC408153
EDAT- 1999/03/17 00:00
MHDA- 1999/03/17 00:01
CRDT- 1999/03/17 00:00
PHST- 1999/03/17 00:00 [pubmed]
PHST- 1999/03/17 00:01 [medline]
PHST- 1999/03/17 00:00 [entrez]
AID - 10.1172/JCI6042 [doi]
PST - ppublish
SO  - J Clin Invest. 1999 Mar;103(6):879-87. doi: 10.1172/JCI6042.