Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

BIN2 orchestrates platelet calcium signaling in thrombosis and thrombo-inflammation

Volz, Julia ; Kusch, Charly ; Beck, Sarah ; Popp, Michael ; Vögtle, Timo ; Meub, Mara ; Scheller, Inga ; Heil, Hannah S LU orcid ; Preu, Julia and Schuhmann, Michael K , et al. (2020) In The Journal of clinical investigation 130(11). p.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 (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... (More)

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.

(Less)
Please use this url to cite or link to this publication:
author
; ; ; ; ; ; ; ; and , et al. (More)
; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; and (Less)
publishing date
type
Contribution to journal
publication status
published
keywords
Adaptor Proteins, Signal Transducing/genetics, Animals, Blood Platelets/metabolism, Calcium Signaling, Disease Models, Animal, Inflammation/genetics, Inositol 1,4,5-Trisphosphate Receptors/genetics, Mice, Mice, Transgenic, Stromal Interaction Molecule 1/genetics, Thrombosis/genetics
in
The Journal of clinical investigation
volume
130
issue
11
pages
6064 - 6079
publisher
American Society for Clinical Investigation
external identifiers
  • pmid:32750041
  • scopus:85094974232
ISSN
0021-9738
DOI
10.1172/JCI136457
language
English
LU publication?
no
id
c514b65e-e2f2-4c8f-b5b8-96f7eae518a2
date added to LUP
2025-04-26 12:11:33
date last changed
2025-05-25 07:03:02
@article{c514b65e-e2f2-4c8f-b5b8-96f7eae518a2,
  abstract     = {{<p>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.</p>}},
  author       = {{Volz, Julia and Kusch, Charly and Beck, Sarah and Popp, Michael and Vögtle, Timo and Meub, Mara and Scheller, Inga and Heil, Hannah S and Preu, Julia and Schuhmann, Michael K and Hemmen, Katherina and Premsler, Thomas and Sickmann, Albert and Heinze, Katrin G and Stegner, David and Stoll, Guido and Braun, Attila and Sauer, Markus and Nieswandt, Bernhard}},
  issn         = {{0021-9738}},
  keywords     = {{Adaptor Proteins, Signal Transducing/genetics; Animals; Blood Platelets/metabolism; Calcium Signaling; Disease Models, Animal; Inflammation/genetics; Inositol 1,4,5-Trisphosphate Receptors/genetics; Mice; Mice, Transgenic; Stromal Interaction Molecule 1/genetics; Thrombosis/genetics}},
  language     = {{eng}},
  month        = {{11}},
  number       = {{11}},
  pages        = {{6064--6079}},
  publisher    = {{American Society for Clinical Investigation}},
  series       = {{The Journal of clinical investigation}},
  title        = {{BIN2 orchestrates platelet calcium signaling in thrombosis and thrombo-inflammation}},
  url          = {{http://dx.doi.org/10.1172/JCI136457}},
  doi          = {{10.1172/JCI136457}},
  volume       = {{130}},
  year         = {{2020}},
}