Por favor, use este identificador para citar o enlazar a este item:
http://hdl.handle.net/10261/151195
COMPARTIR / EXPORTAR:
SHARE CORE BASE | |
Visualizar otros formatos: MARC | Dublin Core | RDF | ORE | MODS | METS | DIDL | DATACITE | |
Título: | Critical role for Epac1 in inflammatory pain controlled by GRK2-mediated phosphorylation of Epac1 |
Autor: | Singhmar, Pooja; Mayor Menéndez, Federico CSIC ORCID; Murga, Cristina CSIC ORCID; Kavelaars, Annemieke | Palabras clave: | Epac1 Epac1 translocation Chronic pain Piezo2 GRK2 |
Fecha de publicación: | 15-mar-2016 | Editor: | National Academy of Sciences (U.S.) | Citación: | PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 113: 3036- 3041 (2016) | Resumen: | cAMP signaling plays a key role in regulating pain sensitivity. Here, we uncover a previously unidentified molecular mechanism in which direct phosphorylation of the exchange protein directly activated by cAMP 1 (EPAC1) by G protein kinase 2 (GRK2) suppresses Epac1-to-Rap1 signaling, thereby inhibiting persistent inflammatory pain. Epac1−/− mice are protected against inflammatory hyperalgesia in the complete Freund’s adjuvant (CFA) model. Moreover, the Epac-specific inhibitor ESI-09 inhibits established CFA-induced mechanical hyperalgesia without affecting normal mechanical sensitivity. At the mechanistic level, CFA increased activity of the Epac target Rap1 in dorsal root ganglia of WT, but not of Epac1−/−, mice. Using sensory neuronspecific overexpression of GRK2 or its kinase-dead mutant in vivo, we demonstrate that GRK2 inhibits CFA-induced hyperalgesia in a kinase activity-dependent manner. In vitro, GRK2 inhibits Epac1-to-Rap1 signaling by phosphorylation of Epac1 at Ser-108 in the Disheveled/ Egl-10/pleckstrin domain. This phosphorylation event inhibits agonist-induced translocation of Epac1 to the plasma membrane, thereby reducing Rap1 activation. Finally, we show that GRK2 inhibits Epac1-mediated sensitization of the mechanosensor Piezo2 and that Piezo2 contributes to inflammatory mechanical hyperalgesia. Collectively, these findings identify a key role of Epac1 in chronic inflammatory pain and a molecular mechanism for controlling Epac1 activity and chronic pain through phosphorylation of Epac1 at Ser-108. Importantly, using the Epac inhibitor ESI-09, we validate Epac1 as a potential therapeutic target for chronic pain. | URI: | http://hdl.handle.net/10261/151195 | DOI: | 10.1073/pnas.1516036113 | Identificadores: | doi: 10.1073/pnas.1516036113 issn: 0027-8424 |
Aparece en las colecciones: | (CBM) Artículos |
Ficheros en este ítem:
Fichero | Descripción | Tamaño | Formato | |
---|---|---|---|---|
MurgaC_CriticalRoleForEpac1InInflamatory.pdf | 1,07 MB | Adobe PDF | Visualizar/Abrir |
CORE Recommender
PubMed Central
Citations
70
checked on 01-abr-2024
SCOPUSTM
Citations
101
checked on 23-abr-2024
WEB OF SCIENCETM
Citations
88
checked on 22-feb-2024
Page view(s)
302
checked on 21-abr-2024
Download(s)
185
checked on 21-abr-2024
Google ScholarTM
Check
Altmetric
Altmetric
Artículos relacionados:
NOTA: Los ítems de Digital.CSIC están protegidos por copyright, con todos los derechos reservados, a menos que se indique lo contrario.