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Protease-activated receptor 1 (PAR1) signalling desensitization is counteracted via PAR4 signalling in human platelets
Department of Clinical and Experimental Medicine, University of Linköping, University Hospital, Linköping, Sweden.
Department of Medical and Health Sciences, University of Linköping, University Hospital, Linköping, Sweden.
Department of Medical and Health Sciences, University of Linköping, University Hospital, Linköping, Sweden.
Department of Clinical and Experimental Medicine, University of Linköping, University Hospital, Linköping, Sweden.
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2011 (English)In: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 436, no 2, p. 469-480Article in journal (Refereed) Published
Abstract [en]

PARs (protease-activated receptors) 1 and 4 belong to the family of G-protein-coupled receptors which induce both G(α12/13) and G(αq) signalling. By applying the specific PAR1- and PAR4-activating hexapeptides, SFLLRN and AYPGKF respectively, we found that aggregation of isolated human platelets mediated via PAR1, but not via PAR4, is abolished upon homologous receptor activation in a concentration- and time-dependent fashion. This effect was not due to receptor internalization, but to a decrease in Ca²⁺ mobilization, PKC (protein kinase C) signalling and α-granule secretion, as well as to a complete lack of dense granule secretion. Interestingly, subthreshold PAR4 activation rapidly abrogated PAR1 signalling desensitization by differentially reconstituting these affected signalling events and functional responses, which was sufficient to re-establish aggregation. The lack of ADP release and P2Y₁₂ receptor-induced G(αi) signalling accounted for the loss of the aggregation response, as mimicking G(αi/z) signalling with 2-MeS-ADP (2-methylthioadenosine-5'-O-diphosphate) or epinephrine (adrenaline) could substitute for intermediate PAR4 activation. Finally, we found that the re-sensitization of PAR1 signalling-induced aggregation via PAR4 relied on PKC-mediated release of both ADP from dense granules and fibrinogen from α-granules. The present study elucidates further differences in human platelet PAR signalling regulation and provides evidence for a cross-talk in which PAR4 signalling counteracts mechanisms involved in PAR1 signalling down-regulation.

Place, publisher, year, edition, pages
2011. Vol. 436, no 2, p. 469-480
Keywords [en]
ADP; Desensitization; P2Y12 receptor; Platelet; Protease-activated receptor (PAR); Protein kinase C (PKC)
National Category
Cell and Molecular Biology Pharmacology and Toxicology
Research subject
Molecular Biology; Biochemistry
Identifiers
URN: urn:nbn:se:oru:diva-42397DOI: 10.1042/BJ20101360ISI: 000291413200027PubMedID: 21391917Scopus ID: 2-s2.0-79956052911OAI: oai:DiVA.org:oru-42397DiVA, id: diva2:786043
Note

Funding Agencies:

County Council of Östergötland K2010-65X-15060-07-3

University of Linköping

Medical Faculty of the University of Linköping through Forsknings- och Forskarutbildningsnämnden (FUN)

Available from: 2015-02-04 Created: 2015-02-04 Last updated: 2018-01-11Bibliographically approved

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