Disease relevance of Stxbp3a

• Recombinant expression of Munc18c in a baculovirus system and interaction with syntaxin4 [1].

High impact information on Stxbp3a

• Adipocytes from Munc18c-null mice show increased sensitivity to insulin-stimulated GLUT4 externalization [2].
• We have now generated mouse embryos deficient in the syntaxin4 binding protein Munc18c and show that the insulin-induced appearance of GLUT4 at the cell surface is enhanced in adipocytes derived from these Munc18c-/- mice compared with that in Munc18c+/+ cells [2].
• Phosphatidylinositol 3-phosphate, which induced GLUT4 translocation to the cell periphery without externalization in Munc18c+/+ cells, elicited GLUT4 externalization in Munc18c-/- cells [2].
• To examine the temporal relationship between pre- and post-docking events, we generated a Munc18c temperature-sensitive mutant (Munc18c/TS) by substitution of arginine 240 with a lysine residue [3].
• Munc18c function is required for insulin-stimulated plasma membrane fusion of GLUT4 and insulin-responsive amino peptidase storage vesicles [4].

Biological context of Stxbp3a

• To define the molecular machinery required for platelet exocytosis, we analyzed platelets from Munc18c heterozygous knockout mice [5].
• Munc18c phosphorylation was localized to the N-terminal 255 residues [6].
• Insulin resistance in tetracycline-repressible Munc18c transgenic mice [7].
• Taken together, these results indicate that balance, more than absolute abundance, of Munc18c and Syn4 proteins directly affects whole-body glucose homeostasis through alterations in insulin secretion and insulin action [7].
• Munc18c transgenic mice exhibited approximately 40% decreases in whole-body glycogen/lipid synthesis, skeletal muscle glycogen synthesis, and glycolysis [7].

Anatomical context of Stxbp3a

• No differences in the rates of aggregation or of secretion of [(3)H]-5HT (dense core granules), platelet factor 4 (alpha-granules), or hexosaminidase (lysosomes) were detected between platelets from Munc18c heterozygous knockout or wild-type mice [5].
• Furthermore, endogenous Munc18c was predominantly localized to the plasma membrane and its distribution was not altered by insulin stimulation [8].
• Munc18c(-/+) mice displayed significantly decreased insulin sensitivity in an insulin tolerance test and a >50% reduction in skeletal muscle insulin-stimulated GLUT4 translocation when compared with wild-type (WT) mice [9].
• Munc-18b had a similar distribution to Munc-18c and so may also be involved in vesicle transport to the cell surface, whereas Munc-18a was undetectable by immunoblotting in adipocytes [10].
• Munc18-2 was localised to secretory granules, whereas Munc18-3 was found on the plasma membrane [11].

Associations of Stxbp3a with chemical compounds

• However, after consuming a high-fat diet for only 5 weeks, the Munc18c(-/+) mice manifested severely impaired glucose tolerance compared with high-fat-fed WT mice [9].
• Stimulus-induced tyrosine phosphorylation of Munc18c was investigated as a potential regulatory mechanism by which the Munc18c-Syntaxin 4 complex can be dissociated in response to divergent stimuli in multiple cell types [6].
• Use of [(32)P]orthophosphate incorporation, pervanadate treatment, and phosphotyrosine-specific antibodies demonstrated that Munc18c underwent tyrosine phosphorylation [6].
• Glucose intolerance in Munc18c transgenic mice was reversed by repression of transgene expression using tetracycline or by simultaneous overexpression of Syn4 protein [7].
• In conclusion, our data suggest that the mechanism by which glucosamine inhibits insulin-stimulated GLUT4 translocation involves modification of Munc18c [12].
• When overexpressed in MIN6 cells, this Hc-linker region functioned as a competitive inhibitor of endogenous syntaxin 4-Munc18c binding, increased syntaxin 4 binding to VAMP2, and significantly enhanced glucose-stimulated secretion [13].

Physical interactions of Stxbp3a

• As expected, overexpressed Munc18c was found to co-immunoprecipitate with syntaxin 4 in the basal state [8].
• Together, these data suggest that Munc18c inhibits the docking/fusion of GLUT4-containing vesicles by blocking the binding of VAMP2 to syntaxin 4 [8].
• Supporting the notion of Munc18c binding with Syntaxin 4 and Doc2beta in mutually exclusive complexes, in vitro competition with Syntaxin 4 effectively displaced Munc18c from binding to Doc2beta [14].

Regulatory relationships of Stxbp3a

• Expression of either wild-type Munc18c or the Y521A-Munc18c mutant both resulted in a marked inhibition of insulin-stimulated Glut4 translocation [15].

Other interactions of Stxbp3a

• Munc-18c is 51% identical to Munc-18 and is ubiquitously expressed [16].
• Mutagenesis of one residue in this region, Y219F, significantly increased the affinity of Munc18c for Syntaxin 4, whereas mutation of three other candidate sites was without effect [6].
• These data suggest that syntaxin-4/Munc-18c/VAMP-2 may play a role in the docking/fusion of intracellular GLUT-4-containing vesicles with the cell surface in adipocytes [10].
• Glucosamine-induced insulin resistance is coupled to O-linked glycosylation of Munc18c [12].

Analytical, diagnostic and therapeutic context of Stxbp3a

• His-tagged Munc18c was purified to homogeneity using both cobalt-chelating affinity chromatography and gel filtration chromatography [1].

References