Rab27a mediates the tight docking of insulin granules onto the plasma membrane during glucose stimulation.
The monomeric small GTPase Rab27a is specifically localized on both secretory granules and lysosome-related organelles. Although natural mutations of the Rab27a gene in human Griscelli syndrome and in ashen mice cause partial albinism and immunodeficiency reflecting the dysfunction of lysosome-related organelles, phenotypes resulting from the defective exocytosis of secretory granules have not been reported. To explore the roles of Rab27a in secretory granules, we analyzed insulin secretion profiles in ashen mice. Ashen mice showed glucose intolerance after a glucose load without signs of insulin resistance in peripheral tissues or insulin deficiency in the pancreas. Insulin secretion from isolated islets was decreased specifically in response to high glucose concentrations but not other nonphysiological secretagogues such as high K+ concentrations, forskolin, or phorbol ester. Neither the intracellular Ca2+ concentration nor the dynamics of fusion pore opening after glucose stimulation were altered. There were, however, marked reductions in the exocytosis from insulin granules predocked on the plasma membrane and in the replenishment of docked granules during glucose stimulation. These results provide the first genetic evidence to our knowledge for the role of Rab27a in the exocytosis of secretory granules and suggest that the Rab27a/effector system mediates glucose-specific signals for the exocytosis of insulin granules in pancreatic beta cells.
Kasai
Kazuo
K
Department of Molecular Medicine, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan.
Ohara-Imaizumi
Mica
M
Takahashi
Noriko
N
Mizutani
Shin
S
Zhao
Shengli
S
Kikuta
Toshiteru
T
Kasai
Haruo
H
Nagamatsu
Shinya
S
Gomi
Hiroshi
H
Izumi
Tetsuro
T
D000417:Albinism / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D002273:Carcinogens / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D005089:Exocytosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D005947:Glucose / Q000378:metabolism*; D007153:Immunologic Deficiency Syndromes / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D051379:Mice; D009154:Mutation; D009924:Organ Culture Techniques; D011188:Potassium / Q000378:metabolism; D012326:RNA Splicing / Q000235:genetics; D022142:Secretory Vesicles / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D000075745:rab27 GTP-Binding Proteins
D002273:Carcinogens; D007328:Insulin; D000075745:rab27 GTP-Binding Proteins; D005576:Colforsin; C512962:Rab27a protein, mouse; D020691:rab GTP-Binding Proteins; D005947:Glucose; D013755:Tetradecanoylphorbol Acetate; D011188:Potassium