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The ATP-gated P2X1 ...
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Grenegård, MagnusLinköpings universitet,Farmakologi,Hälsouniversitetet
(author)
The ATP-gated P2X1 receptor plays a pivotal role in activation of aspirin-treated platelets by thrombin and epinephrine
- Article/chapterEnglish2008
Publisher, publication year, extent ...
Numbers
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LIBRIS-ID:oai:DiVA.org:uu-16911
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https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-16911URI
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https://doi.org/10.1074/jbc.M800358200DOI
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https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-20726URI
Supplementary language notes
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Language:English
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Summary in:English
Part of subdatabase
Classification
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Subject category:ref swepub-contenttype
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Subject category:art swepub-publicationtype
Notes
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Human platelets express protease-activated receptor 1 (PAR1) and PAR4 but limited data indicate for differences in signal transduction. We studied the involvement of PAR1 and PAR4 in the cross-talk between thrombin and epinephrine. The results show that epinephrine acted via alpha(2A)-adrenergic receptors to provoke aggregation, secretion, and Ca(2+) mobilization in aspirin-treated platelets pre-stimulated with subthreshold concentrations of thrombin. Incubating platelets with antibodies against PAR4 or the PAR4-specific inhibitor pepducin P4pal-i1 abolished the aggregation. Furthermore, platelets pre-exposed to the PAR4-activating peptide AYPGKF, but not to the PAR1-activating peptide SFLLRN, were aggregated by epinephrine, whereas both AYPGKF and SFLLRN synergized with epinephrine in the absence of aspirin. The roles of released ATP and ADP were elucidated by using antagonists of the purinergic receptors P2X(1), P2Y(1), and P2Y(12) (i.e. NF449, MRS2159, MRS2179, and cangrelor). Intriguingly, ATP, but not ADP, was required for the epinephrine/thrombin-induced aggregation. In Western blot analysis, a low concentration of AYPGKF, but not SFLLRN, stimulated phosphorylation of Akt on serine 473. Moreover, the phosphatidyl inositide 3-kinase inhibitor LY294002 antagonized the effect of epinephrine combined with thrombin or AYPGKF. Thus, in aspirin-treated platelets, PAR4, but not PAR1, interacts synergistically with alpha(2A)-adrenergic receptors, and the PI3-kinase/Akt pathway is involved in this cross-talk. Furthermore, in PAR4-pretreated platelets, epinephrine caused dense granule secretion, and subsequent signaling from the ATP-gated P2X(1)-receptor and the alpha(2A)-adrenergic receptor induced aggregation. These results suggest a new mechanism that has ATP as a key element and circumvents the action of aspirin on epinephrine-facilitated PAR4-mediated platelet activation.
Subject headings and genre
Added entries (persons, corporate bodies, meetings, titles ...)
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Vretenbrant-Öberg, KarinLinköpings universitet,Klinisk kemi,Hälsouniversitetet(Swepub:liu)karvr93
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Nylander, MartinaLinköpings universitet,Farmakologi,Hälsouniversitetet(Swepub:liu)marny97
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Désilets, StéphanieLinköpings universitet,Farmakologi,Hälsouniversitetet(Swepub:liu)stede87
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Lindström, Eva GLinköpings universitet,Farmakologi,Hälsouniversitetet(Swepub:liu)evali73
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Larsson, AndersUppsala universitet,Institutionen för medicinska vetenskaper,Biokemisk struktur och funktion,Department of Medical Sciences, University Hospital, Uppsala SE-75105, Sweden(Swepub:uu)andlarss
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Ramström, IdaLinköpings universitet,Farmakologi,Hälsouniversitetet,Landstinget i Östergötland
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Ramström, SofiaLinköpings universitet,Klinisk kemi,Hälsouniversitetet(Swepub:liu)sofra86
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Lindahl, Tomas LÖstergötlands Läns Landsting,Linköpings universitet,Klinisk kemi,Hälsouniversitetet(Swepub:liu)tomli13
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Linköpings universitetFarmakologi
(creator_code:org_t)
Related titles
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In:Journal of Biological Chemistry283:27, s. 18493-185040021-92581083-351X
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