Gelsolin Modulates Platelet Dense Granule Secretion and Hemostasis via the Actin Cytoskeleton.

Background And Objective:  The mechanisms underlying platelet granule release are not fully understood. The actin cytoskeleton serves as the platelet's structural framework that is remodeled upon platelet activation. Gelsolin is a calcium-dependent protein that severs and caps existing actin filaments although its role in modulating platelet granule exocytosis is unknown.

Methods:  The hemostatic function of wild-type () and gelsolin null ( ) mice was measured ex vivo by rotational thromboelastometry analysis of whole blood. Platelets were purified from and mouse blood and activated with thrombin. Platelet aggregation was assessed by light-transmission aggregometry. Clot retraction was measured to assess outside-in integrin signaling. Adenosine triphosphate (ATP) release and surface P-selectin were measured as markers of dense- and α-granule secretion, respectively.

Results:  The kinetics of agonist-induced aggregation, clot retraction, and ATP release were accelerated in platelets relative to . However, levels of surface P-selectin were diminished in platelets. ATP release was also accelerated in platelets pretreated with the actin-depolymerizing drug cytochalasin D, thus mimicking the kinetics observed in platelets. Conversely, ATP release kinetics were normalized in platelets treated with the actin polymerization agonist jasplakinolide. Rab27b and Munc13-4 are vesicle-priming proteins known to promote dense granule secretion. Co-immunoprecipitation indicates that the association between Rab27b and Munc13-4 is enhanced in platelets.

Conclusions:  Gelsolin regulates the kinetics of hemostasis by modulating the platelet's actin cytoskeleton and the protein machinery of dense granule exocytosis.