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Fusion pore regulation by cAMP/Epac2 controls cargo release during insulin exocytosis
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.ORCID iD: 0000-0003-4453-1498
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.ORCID iD: 0000-0001-9400-6494
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.ORCID iD: 0000-0001-8893-7348
Univ Bergen, Dept Biomed, Bergen, Norway.
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2019 (English)In: eLIFE, E-ISSN 2050-084X, Vol. 8, article id e41711Article in journal (Refereed) Published
Abstract [en]

Regulated 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.

Place, publisher, year, edition, pages
ELIFE SCIENCES PUBLICATIONS LTD , 2019. Vol. 8, article id e41711
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Cell Biology
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URN: urn:nbn:se:uu:diva-389824DOI: 10.7554/eLife.41711ISI: 000471123300001PubMedID: 31099751OAI: oai:DiVA.org:uu-389824DiVA, id: diva2:1339463
Funder
Novo NordiskSwedish Research Council, 2014-02575Swedish Research Council, 2017-00956Swedish Research Council, 2018-02871Ernfors FoundationSwedish Society for Medical Research (SSMF)The Research Council of NorwaySwedish Diabetes AssociationEXODIAB - Excellence of Diabetes Research in SwedenThe Swedish Brain FoundationAvailable from: 2019-07-29 Created: 2019-07-29 Last updated: 2019-07-29Bibliographically approved

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Gucek, AlenkaGandasi, Nikhil ROmar-Hmeadi, MuhmmadTengholm, AndersBarg, Sebastian
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