title: Syntaxin 4 expression affects glucose transporter 8 translocation and embryo survival.
abstract: Target-soluble N-ethylmaleimide-sensitive factor attachment protein receptors (t-SNAREs) are receptors that facilitate vesicle and target membrane fusion. Syntaxin 4 is the t-SNARE critical for insulin-stimulated glucose transporter 4 (GLUT4)-plasma membrane fusion in adipocytes. GLUT8 is a novel IGF-I/insulin-regulated glucose transporter expressed in the mouse blastocyst. Similar to GLUT4, GLUT8 translocates to the plasma membrane to increase glucose uptake at a stage in development when glucose serves as the main substrate. Any decrease in GLUT8 cell surface expression results in increased apoptosis and pregnancy loss. Previous studies have also shown that disruption of the syntaxin 4 (Stx4a) gene results in early embryonic lethality before embryonic d 7.5. We have now demonstrated that syntaxin 4 protein is localized predominantly to the apical plasma membrane of the murine blastocyst. Stx4a inheritance, as detected by protein expression, occurs with the expected Mendelian frequency up to embryonic d 4.5. In parallel, 22% of the blastocysts from Stx4a+/- matings had no significant insulin-stimulated translocation of GLUT8 whereas 77% displayed either partial or complete translocation to the apical plasma membrane. This difference in GLUT8 translocation directly correlated with one-third of blastocysts from Stx4a+/- mating having reduced rates of insulin-stimulated glucose uptake and 67% with wild-type rates. These data demonstrate that the lack of syntaxin 4 expression results in abnormal movement of GLUT8 in response to insulin, decreased insulin-stimulated glucose uptake, and increased apoptosis. Thus, syntaxin 4 functions as the necessary t-SNARE protein responsible for correct fusion of the GLUT8-containing vesicle with the plasma membrane in the mouse blastocyst.
authors.affiliation: Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: Amanda Hoehn
authors.initials: AH
authors.lastname: Wyman
authors.forename: Maggie
authors.initials: M
authors.lastname: Chi
authors.forename: Joan
authors.initials: J
authors.lastname: Riley
authors.forename: Mary O
authors.initials: MO
authors.lastname: Carayannopoulos
authors.forename: Chunmei
authors.initials: C
authors.lastname: Yang
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Coker
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Pessin
authors.forename: Kelle H
authors.initials: KH
authors.lastname: Moley
mesh_terms: D000818:Animals; D017209:Apoptosis; D001755:Blastocyst / Q000502:physiology*; D005260:Female; D015870:Gene Expression; D051246:Glucose Transport Proteins, Facilitative; D007328:Insulin / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009004:Monosaccharide Transport Proteins / Q000378:metabolism*; D011247:Pregnancy; D021381:Protein Transport; D050765:Qa-SNARE Proteins; D050683:R-SNARE Proteins; D051040:Vesicle-Associated Membrane Protein 3
chemical_list: D051246:Glucose Transport Proteins, Facilitative; D007328:Insulin; D008565:Membrane Proteins; D009004:Monosaccharide Transport Proteins; D050765:Qa-SNARE Proteins; D050683:R-SNARE Proteins; C498628:Slc2a8 protein, mouse; D051040:Vesicle-Associated Membrane Protein 3