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Protease-activated ...
Protease-activated receptor 1 (PAR1) signalling desensitization is counteracted via PAR4 signalling in human platelets
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- Fälker, Knut, 1971- (författare)
- Linköpings universitet,Hälsouniversitetet,Klinisk kemi
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- Haglund, Linda (författare)
- Linköpings universitet,Farmakologi,Hälsouniversitetet
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- Gunnarsson, Peter (författare)
- Linköpings universitet,Farmakologi,Hälsouniversitetet
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- Nylander, Martina (författare)
- Linköpings universitet,Farmakologi,Hälsouniversitetet
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- Lindahl, Tomas (författare)
- Östergötlands Läns Landsting,Linköpings universitet,Klinisk kemi,Hälsouniversitetet
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- Grenegård, Magnus (författare)
- Linköpings universitet,Farmakologi,Hälsouniversitetet
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(creator_code:org_t)
- Portland Press -- London, 2011
- 2011
- Engelska.
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Ingår i: Biochemical Journal. - : Portland Press -- London. - 0264-6021 .- 1470-8728. ; 436:2, s. 469-480
- Relaterad länk:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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https://urn.kb.se/re...
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Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmakologi och toxikologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmacology and Toxicology (hsv//eng)
Nyckelord
- ADP; Desensitization; P2Y12 receptor; Platelet; Protease-activated receptor (PAR); Protein kinase C (PKC)
- Molecular Biology
- Molekylärbiologi
- Biochemistry
- Biokemi
- MEDICINE
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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