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receptors (PARs).
35,36
The prototype of these receptors is PAR-1, which is also
known as the thrombin receptor.
Subsequent to the identification of the initial protease-activated receptor
(PAR-1), three additional protease-activated receptors have been identified.
37
The current family of PARs comprises PAR-1, PAR-2,
38
PAR-3,
39
and PAR-
4.
40
Of these, PAR-1, PAR-3, and PAR-4 are activated by thrombin. PAR-2 is
activated by trypsin, tryptase, and coagulation factors VIIa and Xa, but not by
thrombin. It has been established that the ''tethered ligand'' activation para-
digm described below (see Section 2.4.1) applies to all the PARs. There is
considerable species specificity to the nature of PARs on platelets. In primates,
PAR-1 is the main platelet protease-activated receptor. It is also present on
other cells such as endothelial cells, smooth muscle cells, monocytes, and
fibroblasts. PAR-4 is the second PAR on human platelets. Since PAR-4 has
only weak anity for thrombin, it is activated only at high thrombin con-
centrations. It is believed to be a ''rescue receptor'' that is activated in the event
of a serious vascular lesion and the resultant high thrombin concentration.
PAR-3 is found in mouse platelets where it is the major regulator of thrombin
response, along with PAR-4.
41
Since PAR-1 is not present in mouse and rat
platelets, but is present in monkey platelets, non-human primate models have
been used to study the in vivo antithrombotic effects of thrombin receptor
antagonists. However, due to the presence of PAR-1 on rodent coronary artery
smooth muscle cells, rodent models have been used to study the effect of
thrombin receptor antagonists on restenosis and neointimal proliferation.
42
2.4.1 Mechanism of Thrombin Receptor Activation
Although it was known for some time that a thrombin-specific receptor on
platelets mediates platelet activation, the exact mechanism of thrombin-specific
cellular activation was unknown until 1991,
43
when expression cloning of a
functional thrombin receptor was achieved by two groups. These studies also
unveiled the intriguing mechanistic details of the cellular activation of throm-
bin.
44-46
The amino acid sequence deduced from the mRNA encoding the
thrombin receptor revealed a new G-protein-coupled seven-transmembrane
domain receptor with a large extracellular domain.
47
The authors postulated
that thrombin binds to the cellular receptor through its anion binding exo-site
and subsequently cleaves the extracellular domain at Arg41-Ser42 (Figure 2.2).
The newly unmasked amino terminus acts as a ''tethered ligand,'' binding
intramolecularly to the proximal heptahelical segment and eliciting G-protein-
coupled transmembrane signaling.
48,49
Peptides having the sequence Ser-Phe-
Leu-Leu-Arg-Asn, which mimics the new amino terminus of the activated
receptor, function as agonists of PAR-1 and produce functional responses such
as platelet aggregation and mitogenesis.
50
These peptides and their functional
analogs are known as thrombin receptor activating peptides (TRAPs).
Uncleavable mutant thrombin receptors failed to respond to thrombin, but
were responsive to TRAPs.
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