Role of the PAR4 Thrombin Receptor in Stabilizing Platelet-platelet Aggregates as Revealed by a Patient with Hermansky-Pudlak Syndrome

Covic, Lidija; Singh, Christopher R.; Smith, Hedy; Kuliopulos, Athan

doi:10.1055/s-0037-1613071

Cited by 82 publications

(65 citation statements)

References 22 publications

(18 reference statements)

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“…PAR1-dependent formation of platelet-platelet aggregates through the GP IIb/IIIa receptor tends to be transient unless strengthened by additional inputs from the G i -coupled P2Y 12 ADP receptor or from the PAR4 receptor. 12,29,30 PAR4 has evolved a different strategy for interacting with thrombin. Bereft of a high-affinity Hir-like sequence, 31 PAR4 has instead optimized its interactions with the active site of thrombin and uses a negatively charged cluster of amino acid residues to slow dissociation from the positively charged thrombin molecule.…”

Section: The Role Of Pars In Normal Platelet Functionmentioning

confidence: 99%

“…PAR4 is cleaved and signals more slowly but, despite its slower response, generates the majority of the intracellular calcium flux and does not require additional input from the P2Y 12 ADP receptor to form stable platelet-platelet aggregates. 12,30,33 PAR3, the least understood of the protease receptors, acts as a high-affinity thrombin receptor in platelets from most animals other than primates. Rodent platelets lack PAR1 and instead use the PAR3 receptor to enhance thrombin cleavage of the lower-affinity PAR4.…”

Section: The Role Of Pars In Normal Platelet Functionmentioning

confidence: 99%

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Protease-Activated Receptors in Cardiovascular Diseases

2006

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Abstract-Thrombosis associated with the pathophysiological activation of platelets and vascular cells has brought thrombin and its receptors to the forefront of cardiovascular medicine. Thrombin signaling through the protease-activated receptors (PARs) has been shown to influence a wide range of physiological responses including platelet activation, intimal hyperplasia, inflammation, and maintenance of vascular tone and barrier function. The thrombin receptors PAR1 and PAR4 can be effectively targeted in animals in which acute or prolonged exposure to thrombin leads to thrombosis and/or restenosis. In the present study, we describe the molecular and pharmacological basis of small-molecule inhibitors that target PAR1. In addition, we discuss a new class of cell-penetrating inhibitors, termed pepducins, that provide insight into previously unidentified roles of PAR1 and PAR4 in protease signaling. Key Words: arteries Ⅲ endothelium Ⅲ inhibitors Ⅲ platelets Ⅲ receptors Ⅲ signal transduction Ⅲ thrombosis P rotease-activated receptors (PARs) play critical roles in coagulation, inflammation, and vascular homeostasis. [1][2][3][4][5] Proteases that are produced during vascular injury exert many of their cellular effects by cleaving and activating the PARs. Thrombin-dependent platelet activation and aggregation have been shown to be heightened in the setting of angioplasty and stenting, which may cause clinical complications including acute myocardial infarction and death. 6 -8 The high-affinity thrombin receptor PAR1 has long been recognized as an obvious candidate for therapeutic intervention in patients with acute coronary syndromes. It is not yet known, however, whether targeting only PAR1 will achieve sufficient therapeutic efficacy because of the presence of a more recently identified second thrombin receptor named PAR4. 9 -12 PAR1 and PAR2 (a trypsin but not a thrombin receptor) have also been shown to affect other cardiovascular functions such as vasoreactivity and cardiomyocyte hypertrophy.The purpose of the present review is to help the clinical reader understand why PARs are essential for the maintenance of normal vascular integrity. This review will focus on the potential therapeutic utility of targeting the PARs in thrombosis, atherosclerosis, and restenosis. Historically, the PARs have been recalcitrant to the development of peptidomimetic-based antagonists; however, recent PAR1 drug candidates based on natural products are now entering large-scale clinical trials for treatment of patients with acute coronary syndromes. In an orthogonal approach, PARs have also been blocked on the inside of the cell with the use of cell-penetrating pepducins that prevent signaling to internally located G proteins. [13][14][15][16][17] Proof-of-concept experiments in acute thrombosis models point to novel antiplatelet therapies that could potentially benefit patients at risk for acute thrombosis. The Role of PARs in Normal Platelet FunctionPlatelets are essential for proper blood coagulation. Initiation of a platelet thromb...

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Section: The Role Of Pars In Normal Platelet Functionmentioning

confidence: 99%

Section: The Role Of Pars In Normal Platelet Functionmentioning

confidence: 99%

Protease-Activated Receptors in Cardiovascular Diseases

2006

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“…In human platelets, PAR1 and PAR4 have both overlapping and unique signaling functions (9,10). For example, PAR4 activation produces a prolonged signal that is required for stable clot formation (11)(12)(13)(14). Our laboratory has recently mapped the PAR4 homodimer interface to transmembrane helix 4 (15).…”

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confidence: 99%

Protease-activated Receptor 1 (PAR1) and PAR4 Heterodimers Are Required for PAR1-enhanced Cleavage of PAR4 by α-Thrombin

Arachiche

Mumaw

Fuente

et al. 2013

Journal of Biological Chemistry

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Background: Protease-activated receptor 1 (PAR1) and PAR4 mediate thrombin signaling in platelets. Results: Mutations in transmembrane helix 4 (TM4) of PAR1 or PAR4 disrupts ␣-thrombin-induced heterodimerization and PAR1-assisted PAR4 cleavage. Conclusion: PAR1-PAR4 heterodimers are required for efficient PAR4 cleavage. Significance: The dimerization of PAR1 and PAR4 may impact the effectiveness of PAR1 antagonists.

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“…6 However, blockade of only PAR1 may not be sufficient to prevent acute thrombin-mediated platelet aggregation and thrombosis because of the presence of PAR4, the other thrombin receptor present on platelets. [7][8][9] Clinical Perspective p 1254…”

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Blocking the Protease-Activated Receptor 1-4 Heterodimer in Platelet-Mediated Thrombosis

Leger

Jacques²,

Badar³

et al. 2006

Circulation

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Background-Thrombin is the most potent agonist of platelets and plays a critical role in the development of arterial thrombosis. Human platelets express dual thrombin receptors, protease-activated receptor (PAR) 1 and PAR4; however, there are no therapeutic strategies that effectively target both receptors. Methods and Results-Platelet aggregation studies demonstrated that PAR4 activity is markedly enhanced by thrombin-PAR1 interactions. A combination of bivalirudin (hirulog) plus a novel PAR4 pepducin antagonist, P4pal-i1, effectively inhibited aggregation of human platelets to even high concentrations of thrombin and prevented occlusion of carotid arteries in guinea pigs. Likewise, combined inhibition of PAR1 and PAR4 with small-molecule antagonists and pepducins was effective against carotid artery occlusion. Coimmunoprecipitation and fluorescence resonance energy transfer studies revealed that PAR1 and PAR4 associate as a heterodimeric complex in human platelets and fibroblasts. PAR1-PAR4 cofactoring was shown by acceleration of thrombin cleavage and signaling of PAR4 on coexpression with PAR1. Conclusions-We show that PAR1 and PAR4 form a stable heterodimer that enables thrombin to act as a bivalent functional agonist. These studies suggest that targeting the PAR1-PAR4 complex may present a novel therapeutic opportunity to prevent arterial thrombosis.

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Role of the PAR4 Thrombin Receptor in Stabilizing Platelet-platelet Aggregates as Revealed by a Patient with Hermansky-Pudlak Syndrome

Cited by 82 publications

References 22 publications

Protease-Activated Receptors in Cardiovascular Diseases

Protease-Activated Receptors in Cardiovascular Diseases

Protease-activated Receptor 1 (PAR1) and PAR4 Heterodimers Are Required for PAR1-enhanced Cleavage of PAR4 by α-Thrombin

Blocking the Protease-Activated Receptor 1-4 Heterodimer in Platelet-Mediated Thrombosis

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