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

Högberg, Carl LU ; Gidlöf, Olof LU ; Tan, Chanyuan LU ; Svensson, Siv LU ; Öhman, Jenny LU ; Erlinge, David LU and Olde, Björn LU (2011) In Journal of Thrombosis and Haemostasis 9(2). p.361-372
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... (More)
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. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
GPR91, GPCR, PI3K, platelet, succinate, SUCNR1
in
Journal of Thrombosis and Haemostasis
volume
9
issue
2
pages
361 - 372
publisher
Federation of European Neuroscience Societies and Blackwell Publishing Ltd
external identifiers
  • wos:000286626800016
  • pmid:21143371
  • scopus:79251578024
ISSN
1538-7933
DOI
10.1111/j.1538-7836.2010.04158.x
language
English
LU publication?
yes
id
25c2944c-e1e6-4892-9781-cbb4b9e6dea6 (old id 1756567)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/21143371?dopt=Abstract
date added to LUP
2011-01-03 14:38:06
date last changed
2017-11-05 03:19:29
@article{25c2944c-e1e6-4892-9781-cbb4b9e6dea6,
  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.},
  author       = {Högberg, Carl and Gidlöf, Olof and Tan, Chanyuan and Svensson, Siv and Öhman, Jenny and Erlinge, David and Olde, Björn},
  issn         = {1538-7933},
  keyword      = {GPR91,GPCR,PI3K,platelet,succinate,SUCNR1},
  language     = {eng},
  number       = {2},
  pages        = {361--372},
  publisher    = {Federation of European Neuroscience Societies and Blackwell Publishing Ltd},
  series       = {Journal of Thrombosis and Haemostasis},
  title        = {Succinate independently stimulates full platelet activation via cAMP and PI3β kinase signaling.},
  url          = {http://dx.doi.org/10.1111/j.1538-7836.2010.04158.x},
  volume       = {9},
  year         = {2011},
}