Munc18-2, but not Munc18-1 or Munc18-3, regulates platelet exocytosis, hemostasis, and thrombosis

Eduardo I Cardenas, Ricardo Gonzalez, Keegan Breaux, Qi Da, Berenice A Gutierrez, Marco A Ramos, Rodolfo A Cardenas, Alan R Burns, Rolando E Rumbaut, Roberto Adachi

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

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 Caenorhabditis 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 the removal of Munc18-2 ablates the 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.

Original languageEnglish (US)
Pages (from-to)4784-4792
Number of pages9
JournalThe Journal of biological chemistry
Volume294
Issue number13
DOIs
StatePublished - Mar 29 2019
Externally publishedYes

Keywords

  • Animals
  • Blood Platelets/metabolism
  • Disease Models, Animal
  • Exocytosis
  • Hemostasis
  • Mice
  • Mice, Knockout
  • Munc18 Proteins/genetics
  • Secretory Vesicles/genetics
  • Thrombosis/genetics

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