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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Chronic Disease
  • Freund's Adjuvant / toxicity
  • G-Protein-Coupled Receptor Kinase 2 / physiology*
  • Ganglia, Spinal / physiopathology
  • Guanine Nucleotide Exchange Factors / deficiency
  • Guanine Nucleotide Exchange Factors / genetics
  • Guanine Nucleotide Exchange Factors / physiology*
  • Hyperalgesia / etiology
  • Hyperalgesia / physiopathology*
  • Inflammation / chemically induced
  • Inflammation / complications*
  • Ion Channels / physiology
  • Mechanoreceptors / physiology
  • Mice
  • Mice, Knockout
  • Molecular Sequence Data
  • Nerve Tissue Proteins / physiology
  • Nociception / physiology*
  • Pain / etiology
  • Pain / physiopathology*
  • Pain Threshold / physiology
  • Phosphorylation
  • Phosphoserine / metabolism
  • Protein Interaction Mapping
  • Protein Processing, Post-Translational
  • Protein Structure, Tertiary
  • Signal Transduction
  • rap1 GTP-Binding Proteins / physiology


  • Epac protein, mouse
  • Guanine Nucleotide Exchange Factors
  • Ion Channels
  • Nerve Tissue Proteins
  • Piezo2 protein, mouse
  • Phosphoserine
  • Freund's Adjuvant
  • GRK2 protein, mouse
  • G-Protein-Coupled Receptor Kinase 2
  • rap1 GTP-Binding Proteins