Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 288, Issue 19, Pages 13325-13336Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M112.428359
Keywords
-
Categories
Funding
- Cardiovascular Centre, Maastricht
- Center for Translational Molecular Medicine Innovative Coagulation Diagnostics (INCOAG)
- Netherlands Heart Foundation [2011T6]
- National Institute of Health [HL089519]
Ask authors/readers for more resources
Aggregation of platelets via activated integrin alpha(IIb)beta(3) is a prerequisite for thrombus formation. Phosphatidylserine-exposing platelets with a key role in the coagulation process disconnect from a thrombus by integrin inactivation via an unknown mechanism. Here we show that alpha(IIb)beta(3) inactivation in procoagulant platelets relies on a sustained high intracellular Ca2+, stimulating intracellular cleavage of the beta(3) chain, talin, and Src kinase. Inhibition of calpain activity abolished protein cleavage, but only partly suppressed alpha(IIb)beta(3) inactivation. Integrin alpha(IIb)beta(3) inactivation was unchanged in platelets from Capn1(-/-) mice, suggesting a role of the calpain-2 isoform. Scott syndrome platelets, lacking the transmembrane protein TMEM16F and having low phosphatidylserine exposure, displayed reduced alpha(IIb)beta(3) inactivation with the remaining activity fully dependent on calpain. In platelets from Ppif(-/-) mice, lacking mitochondrial permeability transition pore (mPTP) formation, agonist-induced phosphatidylserine exposure and alpha(IIb)beta(3) inactivation were reduced. Treatment of human platelets with cyclosporin A gave a similar phenotype. Together, these data point to a dual mechanism of alpha(IIb)beta(3) inactivation via calpain(-2) cleavage of integrin-associated proteins and via TMEM16F-dependent phospholipid scrambling with an assistant role of mPTP formation.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available