Fusion pore regulation by cAMP/Epac2 controls cargo release during insulin exocytosis
- Uppsala University, Sweden
- University of Bergen, Norway
Abstract
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.
Data availability
Source data file has been provided for Fig 7. All raw data are available on the Dryad Digital Repository (https://doi.org/10.5061/dryad.6b604g8).
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Data from: Fusion pore regulation by cAMP/Epac2 controls cargo release during insulin exocytosisDryad Digital Repository, doi:10.5061/dryad.6b604g8.
Article and author information
Author details
Muhmmad Omar-Hmeadi
Funding
Swedish Research Council (2014-02575)
- Anders Tengholm
- Sebastian Barg
Norwegian Research Council
- Marit Bakke
Helse-Bergen
- Marit Bakke
Olga Jönssons stipend
- Alenka Guček
P O Zetterlingsstiftelse
- Alenka Guček
Swedish Research Council (2017-00956)
- Anders Tengholm
- Sebastian Barg
Swedich Research Council (2018-02871)
- Anders Tengholm
- Sebastian Barg
European Foundation for the Study of Diabetes
- Anders Tengholm
- Sebastian Barg
Diabetes Wellness Network Sweden
- Anders Tengholm
- Sebastian Barg
Swedish Diabetes Society
- Anders Tengholm
- Sebastian Barg
Swedish Society for Medical Research
- Nikhil R Gandasi
Hjärnfonden
- Sebastian Barg
NovoNordisk
- Nikhil R Gandasi
- Anders Tengholm
- Sebastian Barg
Family Ernfors Foundation
- Alenka Guček
- Anders Tengholm
- Sebastian Barg
European Foundation for the Study of Diabetes
- Nikhil R Gandasi
- Anders Tengholm
- Sebastian Barg
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with European and Swedish legislation, fundamental ethical principles and approved by the Regional Ethics Board Uppsala (license number 31, 1-32).
Copyright
© 2019, Guček et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Fusion pore regulation by cAMP/Epac2 controls cargo release during insulin exocytosis
eLife 8:e41711.
https://doi.org/10.7554/eLife.41711
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