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Munc 18-1 and granuphilin collaborate during insulin granule exocytosis
Journal article --- Old month value: Jan 19 --- Old uritopublisher value: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18208509
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 RNAi. 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, over-expression of Munc 18-1 had no effect on insulin secretion. Although there was no detectable interaction between Munc 18-1 and Mint1 or CASK, 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.
autophagy, docking, granuphilin, insulin granule, Munc 18-1, trans Golgi network
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