Q94 is not a selective modulator of proteinase-activated receptor 1 (PAR1) in platelets.
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Francis, L. R., Millington-Burgess, S. L., Rahman, M. T., & Harper, M. (2022). Q94 is not a selective modulator of proteinase-activated receptor 1 (PAR1) in platelets.. Platelets https://doi.org/10.1080/09537104.2022.2026911
Thrombin is a 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+ signaling, 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 were also inhibited with similar potency. Finally, in endothelial cells, Q94 did not inhibit PAR1-dependent Ca2+ signaling. Our data suggest that Q94 may have PAR1-independent off-target effects in platelets, precluding its use as a selective PAR1 allosteric modulator.
British Heart Foundation (project grant PG/20/12/34982)
British Heart Foundation (PG/20/12/34982)
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External DOI: https://doi.org/10.1080/09537104.2022.2026911
This record's URL: https://www.repository.cam.ac.uk/handle/1810/332454
Attribution-NonCommercial 4.0 International
Licence URL: https://creativecommons.org/licenses/by-nc/4.0/