Abstract Number: PB1745
Meeting: ISTH 2020 Congress
Background: Ca2+ signaling is key to cell organization, and its modulation controls many cellular responses. Sarco-endoplasmic reticulum Ca2+-ATPases (SERCAs) pump cytosolic Ca2+ into internal stores that in turn regulate cytosolic Ca2+ concentration rise upon cell activation. Platelets exhibit 2 types of SERCAs, SERCA2b and SERCA3, which may exert specific roles, yet ill-defined. We have recently shown that Ca2+ mobilization from SERCA3-dependent stores was required for full platelet activation in weak stimulation conditions.
Aims: The aim of this study was to uncover the signaling mechanism involved in the mobilization of Ca2+ from SERCA3-dependent stores leading to an early ADP secretion that acts as an autocrine loop to potentiate platelet activation.
Methods: Mouse wild-type or SERCA3-deficient platelets, or human platelets were tested for calcium mobilization, secretion and aggregation in presence of different inhibitors.
Results: We demonstrate that an early (5 to 10 seconds following stimulation) ADP secretion is specifically dependent on SERCA3 stored Ca2+ exclusively mobilized by nicotinic acid adenosine dinucleotide phosphate (NAADP), both being blocked by the NAADP receptor antagonist Ned-19, and conversely stimulated by permeant NAADP. In contrast, Ca2+ mobilization from SERCA3-dependent stores and primary ADP secretion were unaffected by inhibition of the production of inositol-1,4,5-trisphosphate (IP3) by phospholipase-C, and accordingly were not stimulated by permeant IP3. On the contrary, late ADP secretion and SERCA2b-dependent Ca2+ stores mobilization were blocked by phospholipase C inhibition or conversely stimulated by permeant IP3 and not by NAADP. Finally, platelet incubation with NAADP and IP3 triggered ADP secretion to a level comparable to thrombin stimulation.
Conclusions: An early ADP secretion, specifically driven by an NAADP/SERCA3 Ca2+ mobilization pathway, potentiates platelet activation via a secondary wave of ADP secretion driven by an IP3/SERCA2b-dependent Ca2+ stores pathway. Because of its modulating effect on platelet activation, this NAADP-SERCA3 pathway may be a relevant target for future anti-thrombotic therapy.
To cite this abstract in AMA style:Feng M, Elaïb Z, Borgel D, Denis C, Adam F, Bryckaert M, Rosa J-, Bobe R. NAADP/SERCA3-Dependent Ca2+ Stores Pathway Specifically Controls Early Autocrine ADP Secretion Potentiating Platelet Activation [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/naadp-serca3-dependent-ca2-stores-pathway-specifically-controls-early-autocrine-adp-secretion-potentiating-platelet-activation/. Accessed December 5, 2021.
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