Involvement of Munc18 isoforms in the regulation of granule exocytosis in neutrophils

Biochim Biophys Acta. 2008 Oct;1783(10):1781-91. doi: 10.1016/j.bbamcr.2008.05.023. Epub 2008 Jun 6.


Human neutrophil granule exocytosis mobilizes a complex set of secretory granules. This involves different combinations of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins to facilitate membrane fusion. The control mechanisms governing the late fusion steps are still poorly understood. Here, we have analyzed SNARE-interacting Sec1/Munc18 (SM) family members. We found that human neutrophils express Munc18-2 and Munc18-3 isoforms and that Munc18-2 interacts with the target-SNARE syntaxin 3. Munc18-2 was associated preferentially with primary granules but could also be found with secondary and tertiary granules, while Munc18-3 was majorily associated with secondary and tertiary granules. Ultrastructural analysis showed that both Munc18-2 and Munc18-3 were often located in close proximity to their respective SNARE-binding partners syntaxin 3 and syntaxin 4. Both isoforms were also found in plasma membrane fractions and in the cytosol, where they associate with cytoskeletal elements. Upon stimulation, Munc18-2 and Munc18-3 redistributed and became enriched on granules and in the plasma membrane. Munc18-2 primary granule exocytosis can be blocked by introduction of Munc18-2-specific antibodies indicating a crucial role in primary granule fusion. Our results suggest that Munc18-2 acts as a regulator of primary granule exocytosis, while Munc18-3 may preferentially regulate the fusion of secondary granules.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Membrane Permeability
  • Cells, Cultured
  • Cytoplasmic Granules / metabolism*
  • Exocytosis*
  • Humans
  • Microscopy, Electron, Transmission
  • Munc18 Proteins / genetics
  • Munc18 Proteins / metabolism*
  • Munc18 Proteins / ultrastructure
  • Neutrophils / metabolism*
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Protein Transport


  • Munc18 Proteins
  • Protein Isoforms