Critical role for Epac1 in inflammatory pain controlled by GRK2-mediated phosphorylation of Epac1
EntityUAM. Departamento de Biología Molecular
PublisherNational Academy of Sciences
10.1073/pnas.1516036113Proceedings of the National Academy of Sciences of the United States of America 113.11 (2016): 3036-3041
ISSN0027-8424 (print); 1091-6490 (online)
Funded byThis work was supported by National Institutes of Health Grants R01 NS073939, R01 NS074999, R01 GM066170, and R01GM106218 and High-End Instrumentation Program 1S10OD012304-01; Cancer Prevention Research Institute of Texas Core Facility Grant RP130397 (a University of Texas System Science and Technology Acquisition and Retention grant); Ministerio de Economía y Competitividad Grant SAF2014-55511-R; Comunidad de Madrid Grant S2010/BMD-2332 (Inter-Disciplinary Research Network); Ministerio Sanidad y Consumo-Instituto Carlos III Cardiovascular Network Grant RD12/0042/0012; a European Foundation for the Study of Diabetes– Novo Nordisk grant; and by Universidad Autónoma de Madrid–Banco de Santander
ProjectGobierno de España. SAF2014-55511-R; Comunidad de Madrid. S2010/BMD-2332/INDISNET
SubjectsChronic pain; Epac1; Epac1 translocation; GRK2; Piezo2; Biología y Biomedicina / Biología
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
Google Scholar:Singhmar, P. - Huo, X. - Eijkelkamp, N. - Berciano, S.R. - Baameur, F. - Mei, F.C. - Zhu, Y. - Cheng, X. - Hawke, D. - Mayor Menéndez, Federico - Murga Montesinos, Cristina - Heijnen, C.J. - Kavelaars, A.
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