Journal
DIABETES
Volume 66, Issue 10, Pages 2610-2622Publisher
AMER DIABETES ASSOC
DOI: 10.2337/db17-0050
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Funding
- Diabetes Research and Wellness Foundation
- European Foundation for the Study of Diabetes (EFSD-MSD)
- Stiftelsen Familjen Ernfors Fond
- Novo Nordisk Foundation
- Swedish Diabetes Foundation
- Swedish Research Council
- EFSD/Lilly European Diabetes Research Programme
- Swedish Society for Medical Research
- JDRF
- strategic grant consortium Excellence of Diabetes Research in Sweden (EXODIAB)
- European Foundation for the Study of Diabetes [Lilly FS 2016_9, MSD 2014_2] Funding Source: researchfish
- Novo Nordisk Fonden [NNF14OC0010363, NNF14OC0010001, NNF15OC0016260] Funding Source: researchfish
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Epac is a cAMP-activated guanine nucleotide exchange factor that mediates cAMP signaling in various types of cells, including -cells, where it is involved in the control of insulin secretion. Upon activation, the protein redistributes to the plasma membrane, but the underlying molecular mechanisms and functional consequences are unclear. Using quantitative high-resolution microscopy, we found that cAMP elevation caused rapid binding of Epac2A to the -cell plasma membrane, where it accumulated specifically at secretory granules and rendered them more prone to undergo exocytosis. cAMP-dependent membrane binding required the high-affinity cyclic nucleotide-binding (CNB) and Ras association domains, but not the disheveled-Egl-10-pleckstrin domain. Although the N-terminal low-affinity CNB domain (CNB-A) was dispensable for the translocation to the membrane, it was critical for directing Epac2A to the granule sites. Epac1, which lacks the CNB-A domain, was recruited to the plasma membrane but did not accumulate at granules. We conclude that Epac2A controls secretory granule release by binding to the exocytosis machinery, an effect that is enhanced by prior cAMP-dependent accumulation of the protein at the plasma membrane.
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