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Rab27a mediates the tight docking of insulin granules onto the plasma membrane during glucose stimulation
Kazuo Kasai, … , Hiroshi Gomi, Tetsuro Izumi
Kazuo Kasai, … , Hiroshi Gomi, Tetsuro Izumi
Published February 1, 2005
Citation Information: J Clin Invest. 2005;115(2):388-396. https://doi.org/10.1172/JCI22955.
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Article Cell biology

Rab27a mediates the tight docking of insulin granules onto the plasma membrane during glucose stimulation

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Abstract

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 β cells.

Authors

Kazuo Kasai, Mica Ohara-Imaizumi, Noriko Takahashi, Shin Mizutani, Shengli Zhao, Toshiteru Kikuta, Haruo Kasai, Shinya Nagamatsu, Hiroshi Gomi, Tetsuro Izumi

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Figure 1

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Expression of Rab27a, Rab27b, and granuphilin in pancreatic islets. (A) ...
Expression of Rab27a, Rab27b, and granuphilin in pancreatic islets. (A) An equal amount of protein (20 μg) from the pancreatic islets of 17-week-old male C3H/He (lane 1) and ashen mice (lane 2) was separated by electrophoresis for immunoblotting with anti-Rab27a, anti-Rab27b, or anti-granuphilin (αGrp-aC) antibodies. The expression levels of α-tubulin were also examined for normalization. For the immunoblotting with anti-Rab27b and anti–α-tubulin antibodies, 20 μg of protein from the pituitary of C3H/He mice were loaded on lane 3 for the reference. Numbers to the left of each panel are molecular masses in kDa. (B) The pancreas organs of 17-week-old male C3H/He (upper) or ashen mice (lower) were immunostained with anti-granuphilin antibodies (αGrp-N). Granuphilin is distinguishably concentrated along the plasma membrane in ashen β cells (arrowheads) compared with control β cells, although the expression levels are similar. Scale bar: 20 μm.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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