The Platelet Release Reaction: Just when you thought platelet secretion was simple

Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, Kentucky, USA.
Current opinion in hematology (Impact Factor: 3.97). 10/2008; 15(5):537-41. DOI: 10.1097/MOH.0b013e328309ec74
Source: PubMed


In response to agonists produced at vascular lesions, platelets release a host of components from their three granules: dense core, alpha, and lysosome. This releasate activates other platelets, promotes wound repair, and initiates inflammatory responses. Although widely accepted, the specific mechanisms underlying platelet secretion are only now coming to light. This review focuses on the core machinery required for platelet secretion.
Proteomic analyses have provided a catalog of the components released from activated platelets. Experiments using a combination of in-vitro secretion assays and knockout mice have led to assignments of both vesicle-soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptor (v-SNARE) and target membrane SNARE to each of the three secretion events. SNARE knockout mice are also proving to be useful models for probing the role of platelet exocytosis in vivo. Other studies are beginning to identify SNARE regulators, which control when and where SNAREs interact during platelet activation.
A complex set of protein-protein interactions control the membrane fusion events required for the platelet release reaction. SNARE proteins are the core elements but the proteins that control SNARE interactions represent key points at which platelet signaling cascades could affect secretion and thrombosis.

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    • "Thus TPC2 is linked to the endolysosome tethering and fusion machinery. In MKs, TPC2 may interact with PDG-specific Rabs and SNARE proteins during PDG biogenesis (Ren et al., 2008; Graham et al., 2009). Our results predict that TPC2 deficiency would affect platelet function due to defective PDG biogenesis and function. "
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    ABSTRACT: Platelet dense granules (PDGs) are acidic calcium stores essential for normal hemostasis. They develop from late endosomal compartments upon receiving PDG-specific proteins through vesicular trafficking but their maturation process is not well understood. Here, we show two-pore channel 2 (TPC2) is a component of the PDG membrane that regulates PDG luminal pH and the pool of releasable Ca(2+). Using a genetically encoded Ca(2+) biosensor and a pore mutant TPC2 we establish the function of TPC2 in Ca(2+) release from PDGs and the formation of perigranular Ca(2+) nanodomains. For the first time Ca(2+) spikes around PDGs - or any organelle of the endo-lysosome family - are visualized in real time and revealed to precisely mark organelle "kiss-and-run" events. Further, the presence of membranous tubules transiently connecting PDGs is revealed and shown to be dramatically enhanced by TPC2 in a mechanism that requires ion flux through TPC2. "Kiss-and-run" events and tubule connections mediate transfer of membrane proteins and luminal content between PDGs. The results show PDGs utilize previously unknown mechanisms of membrane dynamics and content exchange that are regulated by TPC2. © 2015 by The American Society for Cell Biology.
    Preview · Article · Jul 2015 · Molecular biology of the cell
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    • "New methods have been developed allowing to share the results from biochemistry, laser confocal microscopy, and EM to explain the different steps in PLT activation starting from Ca ++ mobilization of the dense tubular system, the degranulation process of dense gran‐ ules followed by the delivery of the contents of α-granules and lysosomes via docking and fusion of the membranes of granules with the membrane of the OCS using the SNARE machinery [101] "
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    ABSTRACT: Platelet concentrates are produced in order to treat bleeding disorders. They can be provided by apheresis machines or by pooling of buffy coats from four blood donations. During their manufacturing and storage, morphological alterations of platelets occur which can be demonstrated by transmission electron microscopy. Alterations range from slight and reversible changes, such as formation of small cell protrusions and swelling of the surface-connected open canalicular system, to severe structural changes, where platelets undergo transitions from discoid to ameboid shapes as a consequence of platelet activation. These alterations end in delivery of the contents of platelet granules as well as platelet involution caused by apoptosis and necrosis processes denoted as the platelet release reaction. Hereby, the involvement of the network of the open canalicular system, helping to deliver the contents of platelet granules into the surrounding milieu via pores, is distinctly shown by electron tomography. As a consequence of platelet activation, a delivery of differently sized microparticles takes place which is thought to play an important role in the adverse reactions in some recipients of platelet concentrates. In this article, the formation and delivery of platelet microparticles is illustrated by electron tomography. Above all, the ultrastructural features of platelets and megakaryocytes are discussed in the context of the molecular characteristics of the plasma membrane and organelles including the different granules and the expression of receptors engaged in signaling during platelet activation. Starting from the knowledge of the ultrastructure of resting and activated platelets, a score classification is presented, allowing the evaluation of different activation stages in a reproducible manner. Examples of evaluations of platelet concentrates using electron microscopy are briefly reviewed. In the last part, experiments showing the interaction of platelets with bacteria are presented. Using the tracer ruthenium red, for staining of the plasma membrane and the open canalicular system of platelets as well as the bacterial wall, the ability of platelets to adhere and sequestrate bacteria by formation of small aggregates, but also to incorporate them into compartments of the open canalicular system which are separated from the surrounding milieu, was shown. In conclusion, electron micro‐ scopy is an appropriate tool for the investigation of the quality of platelet concentrates. It can efficiently support results on the functional state of platelets obtained by other methods such as flow cytometry and aggregometry.
    Full-text · Chapter · Jan 2015
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    • "It is thought that tomosyn plays a role in anchoring the vesicles to the target membrane before release but the mechanism remains elusive. In platelets, there have been reports of tomosyn expression (Ren et al, 2008) and it has also been found in the transcriptome analysis of human and mouse platelets (Rowley et al, 2011). It is a promising candidate for regulating secretion in platelets, but its role remains to be elucidated. "
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    ABSTRACT: Upon activation by extracellular matrix components or soluble agonists, platelets release in excess of 300 active molecules from intracellular granules. Those factors can both activate further platelets and mediate a range of responses in other cells. The complex microenvironment of a growing thrombus, as well as platelets' roles in both physiological and pathological processes, require platelet secretion to be highly spatially and temporally regulated to ensure appropriate responses to a range of stimuli. However, how this regulation is achieved remains incompletely understood. In this review we outline the importance of regulated secretion in thrombosis as well as in 'novel' scenarios beyond haemostasis and give a detailed summary of what is known about the molecular mechanisms of platelet exocytosis. We also discuss a number of theories of how different cargoes could be released in a tightly orchestrated manner, allowing complex interactions between platelets and their environment.
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