oxidative metabolism. The resulting Increase in ATP/ADP ratio triggers closure of the ATP-sensitive potassium channel (K_ATP) leading to membrane depolarization and opening of voltage-gated calcium channels (VDCC). Rise in calcium concentration induces fusion of insulin-granules with the plasma membrane and SNARE-mediated exocytosis. Exocytosis of insulin-granules is biphasic: an initial rapid release is followed by a slower but sustained second release. The 'triggering' first phase involves granules at or near the plasma membrane - the 'readily releasable pool' (RRP).The mobilization of granules from a 'storage-granule pool' (SGP) along with those already docked underlies the second 'amplifying' phase, largely independent of K_ATP channels. The membrane depolarization that opens VDCC also activates the voltage dependent potassium channels (Kcn) leading to re-polarization of the membrane and closure of VDCC. The t-SNARE Snap25 and Stx1a co-localize and/or interact with all channels to potentiate or modulate their activity. Shown is Snap25 which has been reported to bind to and inhibit Kcn. During calcium triggered membrane fusion, the minimal SNARE complex of Snap25, Stx1a and v-SNARE Vamp2 changes from trans to cis configuration. Proposed calcium sensors include members of the Syt family; Munc proteins regulate aspects of complex assembly. Monomeric G protein Rho/Rac/Cdc42 and Rab mediated pathways regulate cytoskeletal rearrangements, important for vesicular transport, and vesicular trafficking, respectively. Cdc42 and Rac1, Rab27a and Rab3a are co-localized with insulin-granules of one or both phases, their exact role under investigation. The second phase of insulin secretion is less well understood; metabolic coupling factors resulting from cycling of pyruvate in the course of glucose metabolism have been suggested to play a role. NADPH, one such factor, can inhibit Kcn activity. Identification of all components and regulators of the pathway are subjects of intense research. The importance of delineating the molecular details of insulin secretion pathway is heightened by the fact that both release phases are impaired in type II diabetes. To see the ontology report for annotations, GViewer and download, click here

[click to see the ontology report for associated GO term - GO:0030073 and related entry at Reactome - REACT_18325.2]...(less)