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    Regulation of Insulin Granule Turnover in Pancreatic β-Cells by Cleaved ICA512

    Trajkovski, Mirko and Mziaut, H. and Schubert, S. and Kalaidzidis, Y. and Altkruger, A. and Solimena, M. (2008) Regulation of Insulin Granule Turnover in Pancreatic β-Cells by Cleaved ICA512. Journal of Biological Chemistry 283 (48), pp. 33719-33729. ISSN 0021-9258.

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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 β-cells. This process is mediated by secretory granule exocytosis. However, how β-cells keep granule stores relatively constant is still unknown. ICA512 is an intrinsic granule membrane protein, whose cytosolic domain binds β2-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 β2-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 β-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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