ArticleProceedings of the National Academy of Sciences of the United States of America2016
Critical role for Epac1 in inflammatory pain controlled by GRK2-mediated phosphorylation of Epac1.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 89 papers, 1 of them a synthesis that pooled it.
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Who cites it
89 citing papers in PubMed, 1 synthesis or guideline pooled it, 125 citations in OpenAlex.
- Enterochromaffin Cells: Sentinels to Gut Microbiota in Hyperalgesia?Frontiers in cellular and infection microbiology · 2021Pooled it
- PIEZO2 mediates injury-induced tactile pain in mice and humans.Science translational medicine · 2018Trial
- LPA/LPAR signaling drives temporomandibular disorders-like pain through regulating the expression and sensitization of PIEZO2.Science advances · 2026Article
- Epac1 deletion attenuates Müller glial pathological activation and mitigates retinal neurodegeneration in ischemia-induced retinopathy.Journal of advanced research · 2026Article
- Mechanotransduction in the Brain: Soliton Theory, Piezo Receptors and MR Elastography in Headache Pathophysiology.Brain and behavior · 2026Review
- Trigeminal nerve root compression induced neuroinflammatory response promotes mechanical allodynia through the CGRP/SP-Piezo2 axis via CaCellular & molecular biology letters · 2025Article
- PIEZO2 in tumors: from mechanobiological switches to activity-targeted therapies.Journal of experimental & clinical cancer research : CR · 2025Review
- Spinal dorsal horn IGF1 mediates the preventive effect of electroacupuncture on cisplatin-induced peripheral neuropathy via neuronal IGF1R in mice.Chinese medicine · 2025Article
- Role of exchange proteins directly activated by cAMP signaling in vascular remodeling.Pharmacological reviews · 2025Review
- A SUMO-interacting motif in the guanine nucleotide exchange factor EPAC1 is required for subcellular targeting and function.bioRxiv : the preprint server for biology · 2025Article
- The Impact ofViruses · 2025Article
- Phosphorylation of cAMP-Activated Exchange Protein-1 Participates in Neuroprotection and Ferroptosis Regulation Following Intracerebral Hemorrhage in Rats.CNS neuroscience & therapeutics · 2025Article
- Integrative study of lung cancer adeno-to-squamous transition in EGFR TKI resistance identifies RAPGEF3 as a therapeutic target.National science review · 2024Article
- Mechanisms of mechanotransduction and physiological roles of PIEZO channels.Nature reviews. Molecular cell biology · 2024Review
- Celastrol Ameliorates Neuronal Mitochondrial Dysfunction Induced by Intracerebral Hemorrhage via Targeting cAMP-Activated Exchange Protein-1.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Role of EPAC1 in chronic pain.Biochemistry and biophysics reports · 2024Review
- GPCR kinases differentially modulate biased signaling downstream of CXCR3 depending on their subcellular localization.Science signaling · 2024Article
- An Ascending Excitatory Circuit from the Dorsal Raphe for Sensory Modulation of Pain.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2024Article
- cAMP-PKA/EPAC signaling and cancer: the interplay in tumor microenvironment.Journal of hematology & oncology · 2024Review
- The Role of Mechanosensitive Piezo Channels in Chronic Pain.Journal of pain research · 2024Review
29 more citing papers are in PubMed but not listed here.
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Authors and funding
13 authors at 5 institutions in 3 countries.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.