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Biophys J. 2008 Sep;95(5):2226-41. doi: 10.1529/biophysj.107.124990. Epub 2008 May 30.

Identifying the targets of the amplifying pathway for insulin secretion in pancreatic beta-cells by kinetic modeling of granule exocytosis.

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Laboratory of Biological Modeling, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-5621, USA.


A kinetic model for insulin secretion in pancreatic beta-cells is adapted from a model for fast exocytosis in chromaffin cells. The fusion of primed granules with the plasma membrane is assumed to occur only in the "microdomain" near voltage-sensitive L-type Ca(2+)-channels, where [Ca(2+)] can reach micromolar levels. In contrast, resupply and priming of granules are assumed to depend on the cytosolic [Ca(2+)]. Adding a two-compartment model to handle the temporal distribution of Ca(2+) between the microdomain and the cytosol, we obtain a unified model that can generate both the fast granule fusion and the slow insulin secretion found experimentally in response to a step of membrane potential. The model can simulate the potentiation induced in islets by preincubation with glucose and the reduction in second-phase insulin secretion induced by blocking R-type Ca(2+)-channels (Ca(V)2.3). The model indicates that increased second-phase insulin secretion induced by the amplifying signal is controlled by the "resupply" step of the exocytosis cascade. In contrast, enhancement of priming is a good candidate for amplification of first-phase secretion by glucose, cyclic adenosine 3':5'-cyclic monophosphate, and protein kinase C. Finally, insulin secretion is enhanced when the amplifying signal oscillates in phase with the triggering Ca(2+)-signal.

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