Succinate independently stimulates full platelet activation via cAMP and PI3β kinase signaling.

Carl Högberg, Olof Gidlöf, Chanyuan Tan, Siv Svensson, Jenny Öhman, David Erlinge, Björn Olde

Research output: Contribution to journalArticlepeer-review

32 Citations (SciVal)

Abstract

Background: The citric cycle intermediate succinate has recently been identified as ligand for the G-protein coupled receptor (GPCR) SUCNR1. We have previously found that this receptor is one of the most expressed GPCRs in human platelets. Objective: The aim of this study was to investigate the role of SUCNR1 in platelet aggregation and to explore the signalling pathways of this receptor in platelets. Methods and Results: Using RT-PCR, we could demonstrate that SUCNR1 is expressed in human platelets at a level corresponding to that of the P2Y(1) receptor. Light transmission aggregation experiments showed a dose-dependent aggregation induced by succinate reaching a maximum response at 0.5mM. The effect of succinate on platelet aggregation was confirmed with flow cytometry showing increased surface expression of activated GPIIb/IIIa, and P-selectin. Intracellular SUCNR1 signalling was found to result in decreased cAMP levels, Akt phosphorylation mediated by PI3Kβ activation and receptor desensitisation. Further, succinate-induced platelet aggregation was demonstrated to depend on Src, generation of thromboxane A(2) and ATP release. The platelet SUCNR1 is subject to desensitization through both homologous and heterologous mechanisms. In addition, the P2Y(12) receptor inhibitor ticagrelor completely prevented platelet aggregation induced by succinate. Conclusions: Our experiments show that succinate induces full aggregation of human platelets via SUCNR1. Succinate-induced platelet aggregation depends on thromboxane A(2) generation, ATP release and P2Y(12) activation.
Original languageEnglish
Pages (from-to)361-372
JournalJournal of Thrombosis and Haemostasis
Volume9
Issue number2
DOIs
Publication statusPublished - 2011

Subject classification (UKÄ)

  • Cardiac and Cardiovascular Systems

Keywords

  • GPR91
  • GPCR
  • PI3K
  • platelet
  • succinate
  • SUCNR1

Fingerprint

Dive into the research topics of 'Succinate independently stimulates full platelet activation via cAMP and PI3β kinase signaling.'. Together they form a unique fingerprint.

Cite this