title: Syntaxin 2 Acts as Inhibitory SNARE for Insulin Granule Exocytosis.
abstract: Of the four syntaxins specialized for exocytosis, syntaxin (Syn)-2 is the least understood. In this study, we used Syn-2/epimorphin knockout mice to examine the role of Syn-2 in insulin secretory granule (SG) exocytosis. Unexpectedly, Syn-2 knockout mice exhibited paradoxical superior glucose homeostasis resulting from an enhanced insulin secretion. This was confirmed in vitro by pancreatic islet perifusion showing an amplified biphasic glucose-stimulated insulin secretion arising from an increase in size of the readily releasable pool of insulin SGs and enhanced SG pool refilling. The increase in insulin exocytosis was attributed mainly to an enhanced recruitment of the larger pool of newcomer SGs that undergoes no residence time on plasma membrane before fusion and, to a lesser extent, also the predocked SGs. Consistently, Syn-2 depletion resulted in a stimulation-induced increase in abundance of exocytotic complexes we previously demonstrated as mediating the fusion of newcomer SGs (Syn-3/VAMP8/SNAP25/Munc18b) and predocked SGs (Syn-1A/VAMP2/SNAP25/Muncn18a). This work is the first to show in mammals that Syn-2 could function as an inhibitory SNARE protein that, when relieved, could promote exocytosis in pancreatic islet β-cells. Thus, Syn-2 may serve as a potential target to treat diabetes.
authors.affiliation: Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Dan
authors.initials: D
authors.lastname: Zhu
authors.affiliation: Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Li
authors.initials: L
authors.lastname: Xie
authors.affiliation: Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Youhou
authors.initials: Y
authors.lastname: Kang
authors.affiliation: Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Subhankar
authors.initials: S
authors.lastname: Dolai
authors.affiliation: Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Jakob
authors.initials: J
authors.lastname: Bondo Hansen
authors.affiliation: Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Tairan
authors.initials: T
authors.lastname: Qin
authors.affiliation: Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Huanli
authors.initials: H
authors.lastname: Xie
authors.affiliation: Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Tao
authors.initials: T
authors.lastname: Liang
authors.affiliation: Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO.|Department of Developmental Biology, Washington University School of Medicine in St. Louis, St. Louis, MO.
authors.forename: Deborah C
authors.initials: DC
authors.lastname: Rubin
authors.affiliation: Department of Medicine, University of Toronto, Toronto, Ontario, Canada.|Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Lucy
authors.initials: L
authors.lastname: Osborne
authors.affiliation: Department of Medicine, University of Toronto, Toronto, Ontario, Canada herbert.gaisano@utoronto.ca.
authors.forename: Herbert Y
authors.initials: HY
authors.lastname: Gaisano
mesh_terms: D000818:Animals; D015153:Blotting, Western; D005089:Exocytosis / Q000235:genetics*; D005947:Glucose / Q000378:metabolism*; D047468:Immunoprecipitation; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D051938:Munc18 Proteins / Q000378:metabolism; D050765:Qa-SNARE Proteins / Q000378:metabolism; D050683:R-SNARE Proteins / Q000378:metabolism; D050600:SNARE Proteins / Q000378:metabolism*; D022142:Secretory Vesicles / Q000378:metabolism; D013347:Subcellular Fractions; D050825:Synaptosomal-Associated Protein 25 / Q000378:metabolism; D050827:Syntaxin 1 / Q000235:genetics* / Q000378:metabolism; D050988:Vesicle-Associated Membrane Protein 2 / Q000378:metabolism
chemical_list: D007328:Insulin; D051938:Munc18 Proteins; D050765:Qa-SNARE Proteins; D050683:R-SNARE Proteins; D050600:SNARE Proteins; C494209:Snap25 protein, mouse; C494214:Stx1a protein, mouse; C497941:Stxbp2 protein, mouse; D050825:Synaptosomal-Associated Protein 25; D050827:Syntaxin 1; C491831:Vamp8 protein, mouse; D050988:Vesicle-Associated Membrane Protein 2; C494808:vesicle-associated membrane protein 2, mouse; D005947:Glucose