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Protease-activated receptor 1 (PAR1) signalling desensitization is counteracted via PAR4 signalling in human platelets
Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry.
Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
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2011 (English)In: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 436, 469-480 p.Article in journal (Refereed) Published
Abstract [en]

FARs (protease-activated receptors) 1 and 4 belong to the family of G-protein-coupled receptors which induce both G(alpha 12/13) and G(alpha q) 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 Ca(2+) mobilization, PKC (protein kinase C) signalling and alpha-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 P2Y(12) receptor-induced G(alpha i) signalling accounted for the loss of the aggregation response, as mimicking G(alpha i/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 alpha-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
Portland Press -- London , 2011. Vol. 436, 469-480 p.
Keyword [en]
ADP; desensitization; P2Y(12) receptor; platelet; protease-activated receptor (PAR); protein kinase C (PKC)
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-69897DOI: 10.1042/BJ20101360ISI: 000291413200027OAI: oai:DiVA.org:liu-69897DiVA: diva2:433293
Available from: 2011-08-09 Created: 2011-08-08 Last updated: 2017-12-08

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Fälker, KnutGunnarsson, PeterNylander, MartinaLindahl, TomasGrenegård, Magnus

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