BIN2 orchestrates platelet calcium signaling in thrombosis and thrombo-inflammation

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

Abstract

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 (Bin2(fl/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 IP, production were unaltered. This severely defective Ca2+ signaling translated into impaired thrombus formation under flow and a protection of Bin2(fl/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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 0021-9738
• Sprache: Englisch