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Munc18-2, not Munc18-1 or Munc18-3, regulates platelet exocytosis, hemostasis, and thrombosis.
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2019 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, article id jbc.RA118.006922Article in journal (Refereed) Epub ahead of print
Abstract [en]

Platelet degranulation, a form of regulated exocytosis, is crucial for hemostasis and thrombosis. Exocytosis in platelets is mediated by SNARE proteins, and in most mammalian cells this process is controlled by Munc18 (mammalian homolog of C. elegans uncoordinated gene 18) proteins. Platelets express all Munc18 paralogs (Munc18‑1, ‑2, and ‑3), but their roles in platelet secretion and function have not been fully characterized. Using Munc18‑1, ‑2, and ‑3 conditional knockout mice, here we deleted expression of these proteins in platelets and assessed granule exocytosis. We measured products secreted by each type of platelet granule and analyzed EM platelet profiles by design-based stereology. We observed that removal of Munc18‑2 ablates release of alpha, dense, and lysosomal granules from platelets, but we found no exocytic role for Munc18‑1 or ‑3 in platelets. In vitro, Munc18‑2-deficient platelets exhibited defective aggregation at low doses of collagen and impaired thrombus formation under shear stress. In vivo, megakaryocyte-specific Munc18‑2 conditional knockout mice had a severe hemostatic defect and prolonged arterial and venous bleeding times. They were also protected against arterial thrombosis in a chemically-induced model of arterial injury. Taken together, our results indicate that Munc18‑2, but not Munc18‑1 or Munc18‑3, is essential for regulated exocytosis in platelets and platelet participation in thrombosis and hemostasis.

Place, publisher, year, edition, pages
2019. article id jbc.RA118.006922
Keywords [en]
Munc18, SNARE proteins, exocytosis, hemostasis, platelet, secretion, thrombosis
National Category
Cell and Molecular Biology
Research subject
Biomedical Laboratory Science
Identifiers
URN: urn:nbn:se:uu:diva-376459DOI: 10.1074/jbc.RA118.006922PubMedID: 30696774OAI: oai:DiVA.org:uu-376459DiVA, id: diva2:1285766
Available from: 2019-02-05 Created: 2019-02-05 Last updated: 2019-02-05

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Cardenas, Eduardo I

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