title: New Roles of Syntaxin-1A in Insulin Granule Exocytosis and Replenishment.
abstract: In type-2 diabetes (T2D), severely reduced islet syntaxin-1A (Syn-1A) levels contribute to insulin secretory deficiency. We generated β-cell-specific Syn-1A-KO (Syn-1A-βKO) mice to mimic β-cell Syn-1A deficiency in T2D. Glucose tolerance tests showed that Syn-1A-βKO mice exhibited blood glucose elevation corresponding to reduced blood insulin levels. Perifusion of Syn-1A-βKO islets showed impaired first- and second-phase glucose-stimulated insulin secretion (GSIS) resulting from reduction in readily releasable pool and granule pool refilling. To unequivocally determine the β-cell exocytotic defects caused by Syn-1A deletion, EM and total internal reflection fluorescence microscopy showed that Syn-1A-KO β-cells had a severe reduction in the number of secretory granules (SGs) docked onto the plasma membrane (PM) at rest and reduced SG recruitment to the PM after glucose stimulation, the latter indicating defects in replenishment of releasable pools required to sustain second-phase GSIS. Whereas reduced predocked SG fusion accounted for reduced first-phase GSIS, selective reduction of exocytosis of short-dock (but not no-dock) newcomer SGs accounted for the reduced second-phase GSIS. These Syn-1A actions on newcomer SGs were partly mediated by Syn-1A interactions with newcomer SG VAMP8.
authors.affiliation: From the Departments of Medicine.|Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Tao
authors.initials: T
authors.lastname: Liang
authors.affiliation: From the Departments of Medicine.|Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Tairan
authors.initials: T
authors.lastname: Qin
authors.affiliation: From the Departments of Medicine.|Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Li
authors.initials: L
authors.lastname: Xie
authors.affiliation: From the Departments of Medicine.|Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Subhankar
authors.initials: S
authors.lastname: Dolai
authors.affiliation: From the Departments of Medicine.|Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Dan
authors.initials: D
authors.lastname: Zhu
authors.affiliation: Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Kacey J
authors.initials: KJ
authors.lastname: Prentice
authors.affiliation: Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Wheeler
authors.affiliation: From the Departments of Medicine.|Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Youhou
authors.initials: Y
authors.lastname: Kang
authors.affiliation: From the Departments of Medicine.|Molecular Genetics, and.
authors.forename: Lucy
authors.initials: L
authors.lastname: Osborne
authors.affiliation: From the Departments of Medicine, herbert.gaisano@utoronto.ca.|Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Herbert Y
authors.initials: HY
authors.lastname: Gaisano
mesh_terms: D000818:Animals; D005089:Exocytosis; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism; D008297:Male; D051379:Mice; D022142:Secretory Vesicles / Q000378:metabolism*; D050827:Syntaxin 1 / Q000235:genetics / Q000502:physiology*
chemical_list: D007328:Insulin; D050827:Syntaxin 1; D005947:Glucose
keywords: SNARE proteins; Syntaxin-1A; Type 2 diabetes; docking; exocytosis; granule replenishment; insulin secretion; newcomer insulin granule; transgenic mice