Membranes prime the RapGEF EPAC1 to transduce cAMP signaling.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
12 07 2023
12 07 2023
Historique:
received:
20
02
2023
accepted:
30
06
2023
medline:
14
7
2023
pubmed:
13
7
2023
entrez:
12
7
2023
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 37438343
doi: 10.1038/s41467-023-39894-4
pii: 10.1038/s41467-023-39894-4
pmc: PMC10338474
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4157Informations de copyright
© 2023. The Author(s).
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