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First published online March 18, 2009
doi: 10.1242/10.1242/jcs.034355

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Mechanisms of biphasic insulin-granule exocytosis – roles of the cytoskeleton, small GTPases and SNARE proteins

Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA

View larger version (25K): [in this window] [in a new window]   Fig. 1. The stimulus-secretion coupling pathway of glucose-dependent insulin exocytosis. Glucose enters the cells via the GLUT2 transporter (1) and undergoes glycolytic and mitochondrial metabolism (2), which ultimately has the effect of increasing the ATP:ADP ratio (3). An increased ATP:ADP ratio leads to the closure of ATP-sensitive KATP channels (4) and to membrane depolarization (5), which triggers the opening of voltage-dependent Ca2+ channels (VDCCs) (6). The resulting influx of Ca2+ (7) induces the fusion of insulin-containing granules with the plasma membrane and insulin release from the cell (8). PM, plasma membrane.

View larger version (40K): [in this window] [in a new window]   Fig. 2. F-actin reorganization, granule mobilization and glucose-stimulated insulin secretion. Under basal conditions (left panel), F-actin not only functions as a barrier to block SNARE-complex formation, but also supplies transportation tracks for insulin-containing granules. Glucose stimulation (right panel) triggers transient F-actin reorganization to allow the granules access to the plasma membrane (PM) for subsequent docking, fusion (mediated by interactions between VAMP2 and syntaxins) and insulin release.

View larger version (41K): [in this window] [in a new window]   Fig. 3. Granule recruitment supports the second phase of insulin secretion. When present at elevated levels, extracellular glucose enters the islet β-cell through the GLUT2 transporter and rapidly undergoes intracellular metabolism. Through the classic stimulus-secretion coupling pathway, the resulting increase in [Ca2+]i triggers the exocytosis of pre-docked granules in the RRP to give rise to the first phase of insulin secretion (1). Concurrently, the metabolic signal also induces F-actin reorganization (2) and recruits granules to the plasma membrane (PM) to support the sustained second phase of insulin secretion (3).

View larger version (32K): [in this window] [in a new window]   Fig. 4. Roles of small GTPases and their cycling factors in glucose-stimulated insulin secretion. The small Rho-family GTPases Cdc42 and Rac1 are implicated in a common pathway that regulates glucose-induced actin remodeling. Cdc42 has also been implicated in directing granule targeting to t-SNARE sites through its ability to associate directly with VAMP2. The Rab GTPases Rab3A and Rab27A, as well as the Ras-family GTPases RalA and Rap1, have been proposed to function in insulin-granule docking and/or priming. PM, plasma membrane.

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