title: Granuphilin modulates the exocytosis of secretory granules through interaction with syntaxin 1a.
abstract: The molecular mechanism for the regulated exocytosis of dense-core granules in endocrine cells remains relatively uncharacterized compared to that of synaptic vesicles in neurons. A novel set of Rab and its effector, Rab27a/granuphilin, which is localized on insulin granules in pancreatic beta cells, was recently identified. Here we demonstrate that granuphilin directly binds to syntaxin 1a on the plasma membrane, and this interaction is regulated by Rab27a. Granuphilin shows affinity to syntaxin 1a with a closed conformation but not to mutant syntaxin 1a, which adopts an open conformation constitutively. Overexpression of granuphilin significantly enhances basal insulin secretion but profoundly inhibits high K(+)-induced insulin secretion. The effect of granuphilin on insulin secretion was impaired by its mutation that disrupts the binding to either Rab27a or syntaxin 1a. Thus, granuphilin is the first regulator in the exocytotic pathway that functions by directly connecting two critical vesicle transport proteins, Rab and SNARE.
authors.affiliation: Department of Molecular Medicine, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Gunma 371-8512, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Torii
authors.forename: Shengli
authors.initials: S
authors.lastname: Zhao
authors.forename: Zhaohong
authors.initials: Z
authors.lastname: Yi
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Takeuchi
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Izumi
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D002460:Cell Line; D005089:Exocytosis / Q000187:drug effects / Q000502:physiology*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D011188:Potassium / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D011487:Protein Conformation; D050765:Qa-SNARE Proteins; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D050600:SNARE Proteins; D022142:Secretory Vesicles / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D050827:Syntaxin 1; D033921:Vesicular Transport Proteins; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000075745:rab27 GTP-Binding Proteins
chemical_list: D000954:Antigens, Surface; D002352:Carrier Proteins; D007328:Insulin; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D050765:Qa-SNARE Proteins; D011993:Recombinant Fusion Proteins; D050600:SNARE Proteins; C512779:SYTL4 protein, human; C494214:Stx1a protein, mouse; C494213:Stx1a protein, rat; D050827:Syntaxin 1; C122015:Sytl4 protein, mouse; C512778:Sytl4 protein, rat; D033921:Vesicular Transport Proteins; D000075745:rab27 GTP-Binding Proteins; C512962:Rab27a protein, mouse; C512961:Rab27a protein, rat; D020691:rab GTP-Binding Proteins; D011188:Potassium