Q94 is not a selective modulator of proteinase-activated receptor 1 (PAR1) in platelets.
dc.contributor.author | Francis, Luc RA | |
dc.contributor.author | Millington-Burgess, Sarah L | |
dc.contributor.author | Rahman, Taufiq | |
dc.contributor.author | Harper, Matthew T | |
dc.date.accessioned | 2022-01-08T00:30:11Z | |
dc.date.available | 2022-01-08T00:30:11Z | |
dc.date.issued | 2022-10-03 | |
dc.identifier.issn | 0953-7104 | |
dc.identifier.uri | https://www.repository.cam.ac.uk/handle/1810/332454 | |
dc.description.abstract | 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. | |
dc.description.sponsorship | British Heart Foundation (project grant PG/20/12/34982) | |
dc.publisher | Informa UK Limited | |
dc.rights | Attribution-NonCommercial 4.0 International | |
dc.rights.uri | https://creativecommons.org/licenses/by-nc/4.0/ | |
dc.title | Q94 is not a selective modulator of proteinase-activated receptor 1 (PAR1) in platelets. | |
dc.type | Article | |
dc.publisher.department | Department of Pharmacology | |
dc.date.updated | 2022-01-06T09:18:08Z | |
prism.publicationName | Platelets | |
dc.identifier.doi | 10.17863/CAM.79900 | |
dcterms.dateAccepted | 2021-12-24 | |
rioxxterms.versionofrecord | 10.1080/09537104.2022.2026911 | |
rioxxterms.version | AM | |
dc.contributor.orcid | Rahman, Taufiq [0000-0003-3830-5160] | |
dc.identifier.eissn | 1369-1635 | |
rioxxterms.type | Journal Article/Review | |
pubs.funder-project-id | British Heart Foundation (PG/20/12/34982) | |
cam.issuedOnline | 2022-04-13 | |
cam.orpheus.success | Wed May 25 11:13:10 BST 2022 - Embargo updated | |
cam.orpheus.counter | 6 | |
cam.depositDate | 2022-01-06 | |
pubs.licence-identifier | apollo-deposit-licence-2-1 | |
pubs.licence-display-name | Apollo Repository Deposit Licence Agreement | |
rioxxterms.freetoread.startdate | 2023-04-13 |
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