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Munc 18-1 and granuphilin collaborate during insulin granule exocytosis

Pessin, Jeffrey E.
Published in Traffic. 2008, vol. 9, no. 5, p. 813-32
Abstract Munc 18-1 is a member of the Sec/Munc family of syntaxin-binding proteins known to bind to the plasma membrane Q-SNARE syntaxin1 and whose precise role in regulated exocytosis remains controversial. Here, we show that Munc 18-1 plays a positive role in regulated insulin secretion from pancreatic beta cells. Munc 18-1 depletion caused a loss in the secretory capacity of both transiently transfected INS 1E cells and a stable clone with tetracycline-regulated Munc 18-1 RNA interference. In addition, Munc 18-1-depleted cells exhibited defective docking of insulin granules to the plasma membrane and accumulated insulin in the trans Golgi network. Furthermore, glucose stimulation after Munc 18-1 depletion resulted in the rapid formation of autophagosomes. In contrast, overexpression of Munc 18-1 had no effect on insulin secretion. Although there was no detectable interaction between Munc 18-1 and Munc-18-interacting protein 1 or calcium/calmodulin-dependent serine protein kinase, Munc 18-1 associated with the granular protein granuphilin. This association was regulated by glucose and was required for the specific interaction of insulin granules with syntaxin1. We conclude that Munc 18-1 and granuphilin collaborate in the docking of insulin granules to the plasma membrane in an initial fusion-incompetent state, with Munc 18-1 subsequently playing a positive role in a later stage of insulin granule exocytosis.
Keywords AnimalsAnti-Bacterial Agents/metabolismAutophagyCell LineDoxycycline/metabolismExocytosis/physiologyGlucose/metabolismHumansInsulin/metabolismInsulin-Secreting Cells/cytology/metabolismMunc18 Proteins/genetics/metabolismRNA InterferenceRatsSecretory Vesicles/chemistry/metabolismSynaptosomal-Associated Protein 25/metabolismSyntaxin 1/metabolismVacuoles/metabolismVesicle-Associated Membrane Protein 2/metabolismVesicular Transport Proteins/genetics/metabolism
PMID: 18208509
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TOMAS CATALA, Alejandra Del Don et al. Munc 18-1 and granuphilin collaborate during insulin granule exocytosis. In: Traffic, 2008, vol. 9, n° 5, p. 813-32. doi: 10.1111/j.1600-0854.2008.00709.x

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Deposited on : 2009-02-17

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