title: Rim2alpha determines docking and priming states in insulin granule exocytosis.
abstract: Insulin secretion is essential for maintenance of glucose homeostasis, but the mechanism of insulin granule exocytosis, the final step of insulin secretion, is largely unknown. Here, we investigated the role of Rim2alpha in insulin granule exocytosis, including the docking, priming, and fusion steps. We found that interaction of Rim2alpha and Rab3A is required for docking, which is considered a brake on fusion events, and that docking is necessary for K(+)-induced exocytosis, but not for glucose-induced exocytosis. Furthermore, we found that dissociation of the Rim2alpha/Munc13-1 complex by glucose stimulation activates Syntaxin1 by Munc13-1, indicating that Rim2alpha primes insulin granules for fusion. Thus, Rim2alpha determines docking and priming states in insulin granule exocytosis depending on its interacting partner, Rab3A or Munc13-1, respectively. Because Rim2alpha(-/-) mice exhibit impaired secretion of various hormones stored as dense-core granules, including glucose-dependent insulinotropic polypeptide, growth hormone, and epinephrine, Rim2alpha plays a critical role in exocytosis of these dense-core granules.
authors.affiliation: Division of Cellular and Molecular Medicine, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Yasuda
authors.forename: Tadao
authors.initials: T
authors.lastname: Shibasaki
authors.forename: Kohtaro
authors.initials: K
authors.lastname: Minami
authors.forename: Harumi
authors.initials: H
authors.lastname: Takahashi
authors.forename: Akira
authors.initials: A
authors.lastname: Mizoguchi
authors.forename: Yoshitsugu
authors.initials: Y
authors.lastname: Uriu
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Numata
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Mori
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Miyazaki
authors.forename: Takashi
authors.initials: T
authors.lastname: Miki
authors.forename: Susumu
authors.initials: S
authors.lastname: Seino
mesh_terms: D000818:Animals; D005089:Exocytosis / Q000502:physiology*; D019204:GTP-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism; D011188:Potassium / Q000378:metabolism; D022142:Secretory Vesicles / Q000378:metabolism; D050827:Syntaxin 1 / Q000378:metabolism; D020692:rab3 GTP-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020826:rab3A GTP-Binding Protein / Q000378:metabolism
chemical_list: D007328:Insulin; D009419:Nerve Tissue Proteins; C491490:Rims1 protein, mouse; D050827:Syntaxin 1; C503321:Unc13a protein, mouse; D019204:GTP-Binding Proteins; C475524:Rim2 protein, mouse; D020692:rab3 GTP-Binding Proteins; D020826:rab3A GTP-Binding Protein; D011188:Potassium