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Membranes prime the RapGEF EPAC1 to transduce cAMP signaling.
- Source :
-
Nature communications [Nat Commun] 2023 Jul 12; Vol. 14 (1), pp. 4157. Date of Electronic Publication: 2023 Jul 12. - Publication Year :
- 2023
-
Abstract
- EPAC1, a cAMP-activated GEF for Rap GTPases, is a major transducer of cAMP signaling and a therapeutic target in cardiac diseases. The recent discovery that cAMP is compartmentalized in membrane-proximal nanodomains challenged the current model of EPAC1 activation in the cytosol. Here, we discover that anionic membranes are a major component of EPAC1 activation. We find that anionic membranes activate EPAC1 independently of cAMP, increase its affinity for cAMP by two orders of magnitude, and synergize with cAMP to yield maximal GEF activity. In the cell cytosol, where cAMP concentration is low, EPAC1 must thus be primed by membranes to bind cAMP. Examination of the cell-active chemical CE3F4 in this framework further reveals that it targets only fully activated EPAC1. Together, our findings reformulate previous concepts of cAMP signaling through EPAC proteins, with important implications for drug discovery.<br /> (© 2023. The Author(s).)
- Subjects :
- Humans
Cytosol
Membranes
Transducers
Drug Discovery
Heart Diseases
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 14
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 37438343
- Full Text :
- https://doi.org/10.1038/s41467-023-39894-4