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Signaling mechanisms for exocytosis in pancreatic beta cells


Glucose-stimulated insulin secretion (GSIS) ends with exocytosis of the insulin-containing granules, which is dependent on the recruitment and docking of the granules to the plasma membrane. Here we intend to study intracellular mechanisms important for this process, which allow the maintenance of exocytosis. Thus, the hypothesis raised herein is that the reduction of the redox state at the vicinity of the plasma membrane is important for recycling SNAREs proteins after fusion, which seems to be blocked by oxidation. To observe the redox state at the plasma membrane genetically modified redox probes will be combined with Total Internal Reflection Fluorescence (TIRF) microscopy, which isolates the measurements to this specific area. Additionally, exocytosis will be observed via expression of a fluorescent chimeric protein into the granule in combination with patch-clamp to allow the precise electrical control of the cell. Additionally, another important mechanism for exocytosis, would be the acquisition of secretory competence by the granule and by the docking sites at plasma membrane. The signalling pathway mediated by cAMP, which is triggered by glucose during GSIS, appears to be an important candidate to ensure granule recruitment and docking. Combining the expression of a fluorescent protein directed to the granule with TIRF microscopy and patch-clamping we will analyse the importance of cAMP signalling and the role of competence acquisition of granules and docking sites at the membrane for exocytosis. Additionally, the fact that granules attached to the membrane are mainly secreted by strong depolarisations, but not by glucose stimulus, raises the possibility of expression of different calcium sensors in those granules or their mislocation within the secretory domains at the membrane. In summary, this project aims to evaluate the role of intracellular signals generated by glucose as part of the mechanisms for recruitment, docking and fusion of insulin granules. Moreover, it aims to understand the possible resistance to secretion of previously docked granules. This way, we intend to understand the factors that select and direct granules for exocytosis. (AU)

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(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
REBELATO, EDUARDO; SANTOS, LAILA R.; CARPINELLI, ANGELO R.; RORSMAN, PATRIK; ABDULKADER, FERNANDO. Short-term high glucose culture potentiates pancreatic beta cell function. SCIENTIFIC REPORTS, v. 8, . (13/08769-1, 14/14826-0)

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