Syntaxin 8 Regulates Platelet Dense Granule Secretion, Aggregation, and Thrombus Stability

Golebiewska, Ewelina M.; Harper, Matthew T.; Williams, Christopher M.; Savage, Joshua; Goggs, Robert; Mollard, Gabriele Fischer von; Poole, Alastair W.

doi:10.1074/jbc.m114.602615

Cited by 34 publications

(21 citation statements)

References 51 publications

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“…SNAREs and Munc13-4 are required for platelet granule secretion (13–16, 18, 19, 24, 26), but little is known about the step-by-step order of events that culminate in Ca 2+ -activated fusion of granules with the plasma membrane. Previous work from our lab showed that platelet dense granule secretion is ablated in the absence of Munc13-4 while α-granule and lysosomal secretion persist at attenuated rates (24).…”

Section: Discussionmentioning

confidence: 99%

“…Platelets contain a variety of v-SNAREs and t-SNAREs, but previous studies from our laboratory and others suggest that VAMP8 acts as a primary v-SNARE for granule secretion and heterodimer complexes comprising syntaxin-11 and SNAP-23 are key t-SNARE complexes (13–17). Recently, VAMP7 and Syntaxin 8 have been shown to also contribute to platelet exocytosis (18, 19). While SNARE proteins are the core membrane fusion machinery, a host of regulatory proteins affect the timing, location, and Ca 2+ -sensitivity of secretion.…”

Section: Introductionmentioning

confidence: 99%

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Role of Munc13-4 as a Ca2+-dependent tether during platelet secretion

Chicka

Ren

Richards

et al. 2016

Biochemical Journal

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The Munc13 family of exocytosis regulators has multiple Ca2+-binding, C2 domains. Here, we probed the mechanism by which Munc13-4 regulates in vitro membrane fusion and platelet exocytosis. We show that Munc13-4 enhances in vitro SNARE-dependent, proteoliposome fusion in a Ca2+- and phosphatidylserine (PS)-dependent manner that was independent of SNARE concentrations. Munc13-4-SNARE interactions, under the conditions used, were minimal in the absence or presence of Ca2+. However, Munc13-4 was able to bind and cluster liposomes harboring PS in response to Ca2+. Interestingly, Ca2+-dependent liposome binding/clustering and enhancement of proteoliposome fusion required both Munc13-4 C2 domains, but only the Ca2+-liganding aspartate residues of the C2B domain. Analytical ultracentrifugation measurements indicated that, in solution, Munc13-4 was a monomeric prolate ellipsoid with dimensions consistent with a molecule that could bridge two fusing membranes. To address the potential role of Munc13-4 as a tethering protein in platelets, we examined mepacrine-stained, dense granule mobility and secretion in platelets from wild-type and Munc13-4 null (Unc13dJinx) mice. In the absence of Munc13-4, dense granules were highly mobile in both resting and stimulated platelets, and stimulation-dependent granule release was absent. These observations suggest that dense granules are stably docked in resting platelets awaiting stimulation and that Munc13-4 plays a vesicle-stabilizing or tethering role in resting platelets and also in activated platelets in response to Ca2+. In summary, we show that Munc13-4 conveys Ca2+ sensitivity to platelet SNARE-mediated membrane fusion and reveal a potential mechanism by which Munc13-4 bridges and stabilizes apposing membranes destined for fusion. (246 words)

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Role of Munc13-4 as a Ca2+-dependent tether during platelet secretion

Chicka

Ren

Richards

et al. 2016

Biochemical Journal

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“…To explain previous data, Ye et al , showed that the original anti-Syntaxin 2 antibodies, which inhibited release from permeabilized platelets, cross-reacted with Syntaxin 11. Recently, another report demonstrated that Syntaxin 8 influences dense granule but not α-granule or lysosome release [49]. The authors showed that Syntaxin 8 interacts with Syntaxin 11 but not with SNAP-23.…”

Section: T-snares In Plateletsmentioning

confidence: 99%

The nuts and bolts of the platelet release reaction

Joshi

Whiteheart

2016

Platelets

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Secretion is essential to many of the roles that platelets play in the vasculature, e.g., thrombosis, angiogenesis, and inflammation, enabling platelets to modulate the microenvironment at sites of vascular lesions with a myriad of bioactive molecules stored in their granules. Past studies demonstrate that granule cargo release is mediated by Soluble NSF Attachment Protein Receptor (SNARE) proteins, which are required for granule-plasma membrane fusion. Several SNARE regulators, which control when, where, and how the SNAREs interact, have been identified in platelets. Additionally, platelet SNAREs are controlled by post-translational modifications, e.g., phosphorylation and acylation. Although there have been many recent insights into the mechanisms of platelet secretion, much still remains undefined. In this review, we focus on the mechanics of platelet secretion and discuss how the secretory machinery functions in the pathway leading to membrane fusion and cargo release.

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“…The ability of platelets to aggregate is dependent on the release of the granule contents, and this process is facilitated by SNARE proteins at the plasma membrane. 47 VAMP8 mRNA has been shown to be differentially expressed in patients with coronary artery disease due to a SNP in the VAMP8 3'UTR (A->G rs1010). Furthermore, miR-96 is predicted to bind to 3'-UTR of VAMP8 mRNA and has been shown to be expressed in platelets.…”

Section: The Novel Role Of Platelet Rna In Health and Diseasementioning

confidence: 99%

Genomics and transcriptomics of megakaryocytes and platelets: Implications for health and disease

Fisher

Paola

2018

Research and Practice in Thrombosis and Haemostasis

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SummaryThe field of megakaryocyte and platelet biology has been transformed with the implementation of high throughput sequencing. The use of modern sequencing technologies has led to the discovery of causative mutations in congenital platelet disorders and has been a useful tool in uncovering many other mechanisms of altered platelet formation and function. Although the understanding of the presence of RNA in platelets is relatively novel, mRNA and miRNA expression profiles are being shown to play an increasingly important role in megakaryopoiesis and platelet function in normal physiology as well as in disease states. Understanding the genetic perturbations underlying platelet dysfunction provides insight into normal megakaryopoiesis and thrombopoiesis, as well as guiding the development of novel therapeutics.

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Syntaxin 8 Regulates Platelet Dense Granule Secretion, Aggregation, and Thrombus Stability

Cited by 34 publications

References 51 publications

Role of Munc13-4 as a Ca2+-dependent tether during platelet secretion

Role of Munc13-4 as a Ca2+-dependent tether during platelet secretion

The nuts and bolts of the platelet release reaction

Genomics and transcriptomics of megakaryocytes and platelets: Implications for health and disease

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