ADP receptor P2Y12 is the capstone of the cross-talk between Ca 2+ mobilization pathways dependent on ATPases SERCA3 and SERCA2b in platelet
Résumé
Background
Blood platelet Ca2+ stores are regulated by 2 Ca2+-ATPases (SERCA2b and SERCA3). On thrombin stimulation, nicotinic acid adenosine dinucleotide phosphate mobilizes SERCA3-dependent stores, inducing early adenosine 5‘-diphosphate (ADP) secretion, potentiating later SERCA2b-dependent secretion.
Objectives
The aim of this study was to identify which ADP P2 purinergic receptor (P2Y1 and/or P2Y12) is(are) involved in the amplification of platelet secretion dependent on the SERCA3-dependent Ca2+ mobilization pathway (SERCA3 stores mobilization) as triggered by low concentration of thrombin.
Methods
The study used the pharmacologic antagonists MRS2719 and AR-C69931MX, of the P2Y1 and P2Y12, respectively, as well as Serca3-/- mice and mice exhibiting platelet lineage-specific inactivation of the P2Y1 or P2Y12 genes.
Results
We found that in mouse platelets, pharmacological blockade or gene inactivation of P2Y12 but not of P2Y1 led to a marked inhibition of ADP secretion after platelet stimulation with low concentration of thrombin. Likewise, in human platelets, pharmacological inhibition of P2Y12 but not of P2Y1 alters amplification of thrombin-elicited secretion through SERCA2b stores mobilization. Finally, we show that early SERCA3 stores secretion of ADP is a dense granule secretion, based on parallel adenosine triphosphate and serotonin early secretion. Furthermore, early secretion involves a single granule, based on the amount of adenosine triphosphate released.
Conclusion
Altogether, these results show that at low concentrations of thrombin, SERCA3- and SERCA2b-dependent Ca2+ mobilization pathways cross-talk via ADP and activation of the P2Y12, and not the P2Y1 ADP receptor. The relevance in hemostasis of the coupling of the SERCA3 and the SERCA2b pathways is reviewed.
Domaines
Sciences du Vivant [q-bio]
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