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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

1
Laboratory of Neuroimmunology, Department of Symptom Research, University of Texas MD Anderson Cancer Center, Houston, TX 77030;
2
Laboratory of Neuroimmunology and Developmental Origins of Disease, University Medical Center Utrecht, Utrecht 3584 EA, The Netherlands;
3
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;
4
Department of Integrative Biology and Pharmacology and Texas Therapeutics Institute, University of Texas Health Science Center, Houston, TX 77030;
5
Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030.
6
Laboratory of Neuroimmunology, Department of Symptom Research, University of Texas MD Anderson Cancer Center, Houston, TX 77030; akavelaars@mdanderson.org.

Abstract

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.

KEYWORDS:

Epac1; Epac1 translocation; GRK2; Piezo2; chronic pain

PMID:
26929333
PMCID:
PMC4801297
DOI:
10.1073/pnas.1516036113
[Indexed for MEDLINE]
Free PMC Article

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