Functional characterization of SUCNR1, a G-protein coupled receptor with succinate as its specific ligand, suggests that SUCNR1 is part of a novel and physiologically relevant agonist pathway in platelet activation.
“The Bloodomics discovery is very important, as it helps us understand links between platelets and clot formation”, explains Dr. Willem Ouwehand, Bloodomics Project Coordinator and Director of Research and Planning of the ECGF (European Cardiovascular Genetics Foundation). “Now we are trying to understand the impact this and other novel receptors have on the development of heart disease, with the ultimate aim to better prevent heart disease in the future.”
To identify previously unknown platelet receptors Bloodomics compared the transcriptomes of in vitro differentiated megakaryocytes (MKs) and erythroblasts (EBs). RNA was obtained from purified, biologically paired MK and EB cultures and compared using cDNA microarrays.
Bioinformatical analysis of MK upregulated genes identified 151 transcripts encoding transmembrane domain containing proteins. Whilst many of these were known platelet genes, a number of previously unidentified, or poorly characterized, transcripts were also detected. Many of these transcripts, including G6b, G6f, LRRC32, LAT2 and the G-protein coupled receptor SUCNR1, encode proteins with structural features or functions that suggest they may be involved in the modulation of platelet function.
Immunoblotting on platelets confirmed the presence of the encoded proteins, and flow cytometric analysis confirmed the expression of G6b, G6f and LRRC32 on the surface of platelets. Through comparative analysis of expression in platelets and other blood cells the researchers demonstrated that G6b, G6f and LRRC32 are restricted to the platelet lineage, whereas LAT2 and SUCNR1 were also detected in other blood cells.
The identification of the succinate receptor SUCNR1 in platelets is of particular interest, as physiologically relevant concentrations of succinate were shown to potentiate the effect of low doses of a variety of platelet agonists.
The Bloodomics project aims at discovering genetic markers for the prediction of thrombus formation in coronary artery disease and at designing better anti-thrombotics for improved prevention and treatment. The Bloodomics project focuses on the genetics and cell biology of platelets, since it hypothesizes that the response of platelets to plaque rupture is critical in determining whether thrombus formation will lead to arterial blood vessel occlusion.
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