BIN2 orchestrates platelet calcium signaling in thrombosis and thrombo-inflammation.

The Journal of clinical investigation 2020 Nov 02

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Store-operated Ca2+ entry (SOCE) is the major route of Ca2+ influx in platelets. The Ca2+ sensor stromal interaction molecule 1 (STIM1) triggers SOCE by forming punctate structures with the Ca2+ channel Orai1 and the inositol trisphosphate receptor (IP3R), thereby linking the endo-/sarcoplasmic reticulum to the plasma membrane. Here, we identified the BAR domain superfamily member bridging integrator 2 (BIN2) as an interaction partner of STIM1 and IP3R in platelets. Deletion of platelet BIN2 (Bin2fl/fl,Pf4-Cre mice) resulted in reduced Ca2+ store release and Ca2+ influx in response to all tested platelet agonists. These defects were a consequence of impaired IP3R function in combination with defective STIM1-mediated SOC channel activation, while Ca2+ store content and agonist-induced IP3 production were unaltered. This severely defective Ca2+ signaling translated into impaired thrombus formation under flow and a protection of Bin2fl/fl,Pf4-Cre mice in models of arterial thrombosis and stroke. Our results establish BIN2 as a central regulator of platelet activation in thrombosis and thrombo-inflammatory disease settings.

Citation

Julia Volz, Charly Kusch, Sarah Beck, Michael Popp, Timo Vögtle, Mara Meub, Inga Scheller, Hannah S Heil, Julia Preu, Michael K Schuhmann, Katherina Hemmen, Thomas Premsler, Albert Sickmann, Katrin G Heinze, David Stegner, Guido Stoll, Attila Braun, Markus Sauer, Bernhard Nieswandt. BIN2 orchestrates platelet calcium signaling in thrombosis and thrombo-inflammation. The Journal of clinical investigation. 2020 Nov 02;130(11):6064-6079