The platelet release reaction: just when you thought platelet secretion was simple

Section: Introductionmentioning

confidence: 99%

Defective release of α granule and lysosome contents from platelets in mouse Hermansky-Pudlak syndrome models

Meng

Harper

et al. 2015

“…Dense granules contain small molecules, notably adenosine diphosphate (ADP) and adenosine triphosphate (ATP), as well as histamine and serotonin. 21 Upon platelet activation with strong agonists, these granules are first centralized and then secreted, 22,23 which is essential for the recruitment of further platelets, thereby promoting platelet aggregation and thrombus growth.Despite a number of previous studies on the function of Cdc42 in platelets, its role in platelet activation and cytoskeletal reorganization, as well as its impact on degranulation and thrombus formation, is currently unclear. The online version of this article contains a data supplement.…”

mentioning

confidence: 99%

Multiple alterations of platelet functions dominated by increased secretion in mice lacking Cdc42 in platelets

Pleines

Eckly

Elvers

et al. 2010

116

126

Platelet activation at sites of vascular injury is crucial for hemostasis, but it may also cause myocardial infarction or stroke. Cytoskeletal reorganization is essential for platelet activation and secretion. The small GTPase Cdc42 has been implicated as an important mediator of filopodia formation and exocytosis in various cell types, but its exact function in platelets is not established. Here, we show that the megakaryocyte/platelet-specific loss of Cdc42 leads to mild thrombocytopenia and a small increase in platelet size in mice. Unexpectedly, Cdc42-deficient platelets were able to form normally shaped filopodia and spread fully on fibrinogen upon activation, whereas filopodia formation upon selective induction of GPIb signaling was reduced compared with wild-type platelets. Furthermore, Cdc42-deficient platelets showed enhanced secretion of ␣ granules, a higher adenosine diphosphate (ADP)/adenosine triphosphate (ATP) content, increased aggregation at low agonist concentrations, and enhanced aggregate formation on collagen under flow. In vivo, lack of Cdc42 resulted in faster occlusion of ferric chloride-injured arterioles. The life span of Cdc42-deficient platelets was markedly reduced, suggesting increased clearing of the cells under physiologic conditions. These data point to novel multiple functions of Cdc42 in the regulation of platelet activation, granule organization, degranulation, and a specific role in GPIb signaling. (Blood. 2010;115(16): 3364-3373) IntroductionAt sites of tissue trauma, platelets become activated and rapidly aggregate to form a plug that seals the wound and limits blood loss. On the other hand, platelet activation in pathologic situations can lead to thrombosis, causing myocardial infarction or stroke. Platelet activation by multiple signaling pathways leads to shape change, release of intracellularly stored granules, and spreading on immobilized ligands. Small GTPases of the Rho family, namely RhoA, Cdc42, and Rac1, are thought to play important roles in the cytoskeletal rearrangements occurring during platelet activation by facilitating the formation of stress fibers, filopodia and lamellipodia, respectively. 1 In platelets, signaling from G protein-coupled receptors, such as the thromboxane or thrombin receptors, as well as immunoreceptor tyrosine-based activation motif (ITAM)-coupled receptors (GPVI, CLEC-2) was shown to induce activation of Rho GTPases. 2,3 Cdc42 is a small (ϳ 23 kDa) protein that cycles between a GDP-bound inactive and a GTP-bound active state. 4 Cdc42 is an important mediator of filopodia formation in various cell types. According to the "convergent elongation model," active Cdc42 induces activation of Wiskott-Aldrich Syndrome protein (WASP). WASP subsequently activates the ARP2/3 complex, thereby increasing actin turnover and initiating the formation of parallel actin bundles. [5][6][7] Furthermore, Cdc42 can also bind to and activate IRSp53, which recruits the Ena/vasodilator-stimulated phosphoprotein (VASP) family protein Mena, thus promoting filopodi...

“…Platelets contain vesicle-membrane SNAREs (vSNAREs), including VAMP-2, -3, -7, and -8, and target-membrane SNAREs (t-SNAREs), including syntaxin 2, 4, 7, and 11, and SNAP-23, -25 and -29. 4 Studies have shown that syntaxin 2 and SNAP-23 are involved in all 3 platelet granule secretion events, whereas syntaxin 4 mediates ␣-granule and lysosome release. VAMP-8 is the primary v-SNARE required for secretion of all platelet granules.…”

mentioning

confidence: 99%

“…2 The molecular mechanisms involved in platelet granule secretion are complex and incompletely understood. [3][4][5] Platelet activation involves several rapid events, including shape change, aggregation, and granule secretion, and it is difficult to discern the cellular mechanisms involved. Electron microscopy studies have revealed that platelet shape changes are accompanied by cytoskeletal rearrangements and centralization of granules.…”

mentioning

confidence: 99%

Granules and thrombus formation

Kahr

2009

protein transport would sensitize MM cells to proteotoxic stress, providing an attractive explanation for bortezomib's clinical activity and a potential means of identifying bortezomibbased combination approaches that will display even greater antitumor effects. • • • PLATELETS & THROMBOPOIESIS Comment on Graham et al, page 1083 Granules and thrombus formation ----------------------------------------------------------------------------------------------------------------Walter H. A. Kahr UNIVERSITY OF TORONTOIn this issue of Blood, Graham and colleagues demonstrate the importance of platelet dense granule secretion for in vivo platelet accumulation following laser injury, which is mediated by the SNARE protein Endobrevin/VAMP-8. Each human platelet contains 50 to 80 ␣-granules, 3 to 8 dense (␦-) granules, and a few lysosomes. ␣-granules carry more than 300 releasable proteins, including adhesion molecules, chemokines, cytokines, fibrinolytic regulators, immunologic modulators, and an assortment of coagulation, complement, growth, and proangiogenic and antiangiogenic factors. Dense granules contain mostly small molecules, including calcium, magnesium, polyphosphate, ATP, ADP, GTP, GDP, and serotonin. Platelet granule release is important for hemostasis, because patients with inherited granule defects have bleeding problems. ␣-granules are absent in the gray platelet and ARC 1 syndromes, while deficient ␦-granules are observed in isolation, in combination with ␣-granule deficiency, or as part of a syndrome in the Hermansky-Pudlak, Chediak-Higashi, and Griscelli syndromes. 2 The molecular mechanisms involved in platelet granule secretion are complex and incompletely understood. 3-5 Platelet activation involves several rapid events, including shape change, aggregation, and granule secretion, and it is difficult to discern the cellular mechanisms involved. Electron microscopy studies have revealed that platelet shape changes are accompanied by cytoskeletal rearrangements and centralization of granules. Platelet exocytosis involves fusion of granules with the plasma membrane or the open canalicular system (extensive channels of internal membranes that communicate with the outer surface) to release their contents into the extracellular space (see figure). Fusion of granule vesicles requires soluble N-ethylmaleimide-sensitive attachment protein receptors (SNAREs), lipid components, and SNARE regulatory proteins (eg, NSF, Sec1/Munc18 proteins). 6 SNAREs from opposing membranes assemble into a complex consisting of parallel 4-helix bundles, which catalyzes the apposition and fusion of the vesicle with the target membrane. Platelets contain vesicle-membrane SNAREs (vSNAREs), including VAMP-2, -3, -7, and -8, and target-membrane SNAREs (t-SNAREs), including syntaxin 2, 4, 7, and 11, and SNAP-23, -25 and -29. 4 Studies have shown that syntaxin 2 and SNAP-23 are involved in all 3 platelet granule secretion events, whereas syntaxin 4 mediates ␣-granule and lysosome release. VAMP-8 is the primary v-SNARE required for secretion...