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dc.contributor.authorGucek, Alenkaen_US
dc.contributor.authorGandasi, Nikhil R.en_US
dc.contributor.authorOmar-Hmeadi, Muhmmaden_US
dc.contributor.authorBakke, Mariten_US
dc.contributor.authorDoskeland, Stein Oveen_US
dc.contributor.authorTengholm, Andersen_US
dc.contributor.authorBarg, Sebastianen_US
dc.PublishedGucek, Gandasi, Omar-Hmeadi, Bakke M, Doskeland SO, Tengholm A, Barg. Fusion pore regulation by cAMP/Epac2 controls cargo release during insulin exocytosis. eLIFE. 2019;8:e41711eng
dc.description.abstractRegulated exocytosis establishes a narrow fusion pore as initial aqueous connection to the extracellular space, through which small transmitter molecules such as ATP can exit. Co-release of polypeptides and hormones like insulin requires further expansion of the pore. There is evidence that pore expansion is regulated and can fail in diabetes and neurodegenerative disease. Here, we report that the cAMP-sensor Epac2 (Rap-GEF4) controls fusion pore behavior by acutely recruiting two pore-restricting proteins, amisyn and dynamin-1, to the exocytosis site in insulin-secreting beta-cells. cAMP elevation restricts and slows fusion pore expansion and peptide release, but not when Epac2 is inactivated pharmacologically or in Epac2-/- (Rapgef4-/-) mice. Consistently, overexpression of Epac2 impedes pore expansion. Widely used antidiabetic drugs (GLP-1 receptor agonists and sulfonylureas) activate this pathway and thereby paradoxically restrict hormone release. We conclude that Epac2/cAMP controls fusion pore expansion and thus the balance of hormone and transmitter release during insulin granule exocytosis.en_US
dc.publishereLife Sciences Publicationseng
dc.rightsAttribution CC BYeng
dc.titleFusion pore regulation by cAMP/Epac2 controls cargo release during insulin exocytosisen_US
dc.typePeer reviewed
dc.typeJournal article
dc.rights.holderCopyright 2019 The Authors

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