Send to

Choose Destination
Proc Natl Acad Sci U S A. 2016 Mar 15;113(11):3036-41. doi: 10.1073/pnas.1516036113. Epub 2016 Feb 29.

Critical role for Epac1 in inflammatory pain controlled by GRK2-mediated phosphorylation of Epac1.

Author information

Laboratory of Neuroimmunology, Department of Symptom Research, University of Texas MD Anderson Cancer Center, Houston, TX 77030;
Laboratory of Neuroimmunology and Developmental Origins of Disease, University Medical Center Utrecht, Utrecht 3584 EA, The Netherlands;
Departamento de Biología Molecular and Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid-Consejo Superior de Investigaciones Científicas, Madrid 28049, Spain; Instituto de Investigación Sanitaria La Princesa, Madrid 28049, Spain;
Department of Integrative Biology and Pharmacology and Texas Therapeutics Institute, University of Texas Health Science Center, Houston, TX 77030;
Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030.
Laboratory of Neuroimmunology, Department of Symptom Research, University of Texas MD Anderson Cancer Center, Houston, TX 77030;


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 neuron-specific 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.


Epac1; Epac1 translocation; GRK2; Piezo2; chronic pain

[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substances, Grant support

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center