Journal
ELIFE
Volume 8, Issue -, Pages -Publisher
ELIFE SCIENCES PUBLICATIONS LTD
DOI: 10.7554/eLife.41711
Keywords
-
Categories
Funding
- Family Ernfors Foundation
- Uppsala Universitet
- P O Zetterlingsstiftelse
- European Foundation for the Study of Diabetes
- Swedish Society for Medical Research
- Novo Nordisk
- Norwegian Research Council
- Helse-Bergen
- Swedish Research Council [2014-02575, 2017-00956, 2018-02871]
- Diabetes Wellness Network Sweden
- Swedish Diabetes Society
- Exodiab network
- Hjarnfonden
- Swedish Research Council [2017-00956, 2018-02871, 2014-02575] Funding Source: Swedish Research Council
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available