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Q94 is not a selective modulator of proteinase-activated receptor 1 (PAR1) in platelets

Published version
Peer-reviewed

Repository DOI


Type

Article

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Authors

Luc, Francis 
Millington-Burgess, Sarah 
Harper, Matthew 

Abstract

Thrombin is potent platelet activator, acting through proteinase-activated receptors -1 and -4 (PAR1 and PAR4). Of these, PAR-1 is activated more rapidly and by lower thrombin concentrations. Consequently, PAR-1 has been extensively investigated as a target for anti-platelet drugs to prevent myocardial infarction. Q94 has been reported to act as an allosteric modulator of PAR1, potently and selectively inhibiting PAR1-Gαq coupling in multiple cell lines, but its effects on human platelet activation have not been previously studied. Platelet Ca2+ signalling, integrin αIIbβ3 activation and α-granule secretion were monitored following stimulation by a PAR1-activating peptide (PAR1-AP). Although Q94 inhibited these responses, its potency was low compared to other PAR1 antagonists. In addition, αIIbβ3 activation and α-granule secretion in response to other platelet activators was also inhibited with similar potency. Finally, in endothelial cells, Q94 did not inhibit PAR1-dependent Ca2+ signalling. Our data suggest that Q94 may have PAR1-independent off-target effects in platelets, precluding its use as a selective PAR1 allosteric modulator.

Description

Keywords

Allosteric modulator, PAR1, pharmacology, platelets, thrombin, Blood Platelets, Endothelial Cells, Humans, Platelet Activation, Platelet Aggregation, Platelet Glycoprotein GPIIb-IIIa Complex, Receptor, PAR-1, Receptors, Thrombin, Thrombin

Journal Title

Platelets (London)

Conference Name

Journal ISSN

0953-7104
1369-1635

Volume Title

Publisher

Taylor and Francis
Sponsorship
British Heart Foundation (PG/20/12/34982)
British Heart Foundation (project grant PG/20/12/34982)

Version History

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2023-10-12 09:20:43
Published version added
2022-01-08 00:30:11
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