title: Mast cells possess distinct secretory granule subsets whose exocytosis is regulated by different SNARE isoforms.
abstract: Mast cells degranulate and release the contents of intracellular secretory granules in response to the cross-linking of FcepsilonRI by multivalent antigens. These granules contain a variety of biologically active inflammatory mediators; however, it is not clear whether these granules are homogenous or whether there is heterogeneity within the secretory granule population in mast cells. By using genetically altered mice lacking specific vesicle-associated SNARE membrane fusion proteins, we found that VAMP-8-deficient mast cells exhibited defects in FcepsilonRI-regulated exocytosis, whereas synaptobrevin 2- or VAMP-3-deficient mast cells did not. Surprisingly, the defect in secretion in VAMP-8-deficient mice was limited to the subpopulation of mast cell secretory granules containing serotonin and cathepsin D, whereas regulated exocytosis of secretory granules containing histamine and TNF-alpha was normal. Confocal microscopy confirmed that serotonin and histamine were present in distinct intracellular granules and that most serotonin-containing granules were VAMP-8-positive. Thus, this study demonstrates that mast cells do indeed possess distinct subsets of secretory granules and that these subsets use different SNARE isoforms for exocytosis.
authors.affiliation: Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Niti
authors.initials: N
authors.lastname: Puri
authors.forename: Paul A
authors.initials: PA
authors.lastname: Roche
mesh_terms: D000818:Animals; D002402:Cathepsin D / Q000378:metabolism; D002478:Cells, Cultured; D005089:Exocytosis; D017353:Gene Deletion; D008247:Lysosomes / Q000378:metabolism; D008407:Mast Cells / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D020033:Protein Isoforms / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D050600:SNARE Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D022142:Secretory Vesicles / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D020033:Protein Isoforms; D050600:SNARE Proteins; D014409:Tumor Necrosis Factor-alpha; D012701:Serotonin; D002402:Cathepsin D