Fusion Pore Regulation by EPAC2/cAMP Controls Cargo Release during Insulin Exocytosis

Abstract

Regulated exocytosis establishes a narrow fusion pore as the initial aqueous connection to the extracellular space, through which small transmitter molecules such as ATP can exit. Co-release of larger peptides and hormones like insulin requires further expansion of the pore. There is evidence that pore expansion is regulated and can fail in type-2 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 leads to pore expansion and peptide release, but not when Epac2 is inactivated pharmacologically or in Epac2−/− mice. Conversely, overexpression of Epac2 impedes pore expansion. Widely used antidiabetic drugs (GLP-1 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.

Published in

Biophysical Journal
2019, volume: 116, number: 3, Supplement 1, pages: 314A-314A
Publisher: Cell Press

Conference

63rd Annual Meeting of the Biophysical-Society, MAR 02-06, 2019, Baltimore, MD

SLU Authors

• Omar Hmeadi, Muhmmad

  • Uppsala University

UKÄ Subject classification

Cell and Molecular Biology

Publication identifier

• DOI: https://doi.org/10.1016/j.bpj.2018.11.1702

Permanent link to this page (URI)

https://res.slu.se/id/publ/131871