BIN2 orchestrates platelet calcium signaling in thrombosis and thrombo-inflammation

Volz J, Kusch C, Beck S, Popp M, Voegtle T, Meub M, Scheller I, Heil HS, Preu J, Schuhmann MK, Hemmen K, Premsler T, Sickmann A, Heinze KG, Stegner D, Stoll G, Braun A, Sauer M, Nieswandt B (2020)

Publication Type: Journal article

Publication year: 2020

Journal

Journal of Clinical Investigation American Society for Clinical Investigation

Book Volume: 130

Pages Range: 6064-6079

Journal Issue: 11

DOI: 10.1172/JCI136457

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 (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.

Involved external institutions

Universitätsklinikum Würzburg DE Germany (DE) Julius-Maximilians-Universität Würzburg DE Germany (DE) Leibniz-Institut für Analytische Wissenschaften / Leibniz Institute for Analytical Sciences (ISAS) DE Germany (DE)

How to cite

APA:

Volz, J., Kusch, C., Beck, S., Popp, M., Voegtle, T., Meub, M.,... Nieswandt, B. (2020). BIN2 orchestrates platelet calcium signaling in thrombosis and thrombo-inflammation. Journal of Clinical Investigation, 130(11), 6064-6079. https://doi.org/10.1172/JCI136457

MLA:

Volz, Julia, et al. "BIN2 orchestrates platelet calcium signaling in thrombosis and thrombo-inflammation." Journal of Clinical Investigation 130.11 (2020): 6064-6079.

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