A dual thrombin receptor system for platelet activation

Abstract

Platelet-dependent arterial thrombosis triggers most heart attacks and strokes. Because the coagulation protease thrombin is the most potent activator of platelets, identification of the platelet receptors for thrombin is critical for understanding thrombosis and haemostasis. Protease-activated receptor-1 (PAR1) is important for activation of human platelets by thrombin, but plays no apparent role in mouse platelet activation. PAR3 is a thrombin receptor that is expressed in mouse megakaryocytes. Here we report that thrombin responses in platelets from PAR3-deficient mice were markedly delayed and diminished but not absent. We have also identified PAR4, a new thrombin-activated receptor. PAR4 messenger RNA was detected in mouse megakaryocytes and a PAR4-activating peptide caused secretion and aggregation of PAR3-deficient mouse platelets. Thus PAR3 is necessary for normal thrombin responses in mouse platelets, but a second PAR4-mediated mechanism for thrombin signalling exists. Studies with PAR-activating peptides suggest that PAR4 also functions in human platelets, which implies that an analogous dual-receptor system also operates in humans. The identification of a two-receptor system for platelet activation by thrombin has important implications for the development of antithrombotic therapies.

Glycosylation and the activation of proteinase‐activated receptor 2 (PAR2) by human mast cell tryptase

“…Activation occurs by proteolysis of the aminoterminal exodomain resulting in the exposure of a tethered ligand, which presumably binds to, and activates the receptor. There are currently three active members of the PAR family, PAR 1, 2 and 4 (Bohm et al, 1996;Ishihara et al, 1997;Vu et al, 1991;Kahn et al, 1998;Xu et al, 1998). Family member, PAR 3 , has been found to be a co-factor for PAR 4 and as such may not be considered as an active receptor in its own right (Nakanishi-Matsui et al, 2000).…”

Mechanism of trypsin‐induced endothelium‐dependent vasorelaxation in the porcine coronary artery

“…The activation of PAR is initiated by the proteolytic cleavage of its extracellular domain to create the new N-terminus that functions as a tethered ligand (Dery et al, 1998). Four members of PAR, PAR-1, PAR-2, PAR-3 and PAR-4, have so far been isolated and cloned (Ishihara et al, 1997;Kahn et al, 1998;Nystedt et al, 1994;Vu et al, 1991;Xu et al, 1998). PAR-1, PAR-3 and PAR-4 serve as the receptor for thrombin, while PAR-2 and PAR-4 serve as the receptor for trypsin (Nystedt et al, 1994;Xu et al, 1998).…”

Platelets at the vascular interface

“…Thus, it is critical for high sensitivity to thrombin and a fast but reversible integrin activation response. PAR4 binds thrombin with much lower affinity, but it also internalizes more slowly and thus generates a steady and sustained integrin activation signal[16–18]. Similarly, the ADP receptor P2Y1, which is not very abundant on the platelet surface[19], is rapidly desensitized[20,21].…”