Rim2alpha determines docking and priming states in insulin granule exocytosis.
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.
Yasuda
Takao
T
Division of Cellular and Molecular Medicine, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan.
Shibasaki
Tadao
T
Minami
Kohtaro
K
Takahashi
Harumi
H
Mizoguchi
Akira
A
Uriu
Yoshitsugu
Y
Numata
Tomohiro
T
Mori
Yasuo
Y
Miyazaki
Jun-Ichi
J
Miki
Takashi
T
Seino
Susumu
S
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
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