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  Regulation of insulin granule turnover in pancreatic ß-cells by cleaved ICA512

Trajkovski, M., Mziaut, H., Schubert, S., Kalaidzidis, Y., Altkrüger, A., & Solimena, M. (2008). Regulation of insulin granule turnover in pancreatic ß-cells by cleaved ICA512. Journal of Biological Chemistry, 283(48), 33719-33729.

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 Creators:
Trajkovski, Mirko1, Author           
Mziaut, Hassan, Author
Schubert, Sandra2, Author
Kalaidzidis, Yannis1, Author           
Altkrüger, Anke, Author
Solimena, Michele1, Author           
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1Max Planck Institute of Molecular Cell Biology and Genetics, Max Planck Society, ou_2340692              
2Max Planck Society, ou_persistent13              

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 Abstract: Insulin maintains homeostasis of glucose by promoting its uptake into cells from the blood. Hyperglycemia triggers secretion of insulin from pancreatic beta-cells. This process is mediated by secretory granule exocytosis. However, how beta-cells keep granule stores relatively constant is still unknown. ICA512 is an intrinsic granule membrane protein, whose cytosolic domain binds beta2-syntrophin, an F-actin-associated protein, and is cleaved upon granule exocytosis. The resulting cleaved cytosolic fragment, ICA512-CCF, reaches the nucleus and up-regulates the transcription of granule genes, including insulin and ICA512. Here, we show that ICA512-CCF also dimerizes with intact ICA512 on granules, thereby displacing it from beta2-syntrophin. This leads to increased granule mobility and insulin release. Based on these findings, we propose a model whereby the generation of ICA512-CCF first amplifies insulin secretion. The ensuing reduction of granule stores would then increase the probability of newly generated ICA512-CCF to reach the nucleus and enhance granule biogenesis, thus allowing beta-cells to constantly adjust production of granules to their storage size and consumption. Pharmacological modulation of these feedback loops may alleviate deficient insulin release in diabetes.

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 Dates: 2008
 Publication Status: Issued
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 Identifiers: eDoc: 414345
Other: 1049
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Title: Journal of Biological Chemistry
Source Genre: Journal
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Pages: - Volume / Issue: 283 (48) Sequence Number: - Start / End Page: 33719 - 33729 Identifier: -