Epac mediates a cAMP-to-PKC signaling in inflammatory pain: an isolectin B4(+) neuron-specific mechanism
- PMID: 15987941
- PMCID: PMC6725047
- DOI: 10.1523/JNEUROSCI.0285-05.2005
Epac mediates a cAMP-to-PKC signaling in inflammatory pain: an isolectin B4(+) neuron-specific mechanism
Abstract
The epsilon isoform of protein kinase C (PKCepsilon) has emerged as a critical second messenger in sensitization toward mechanical stimulation in models of neuropathic (diabetes, alcoholism, and cancer therapy) as well as acute and chronic inflammatory pain. Signaling pathways leading to activation of PKCepsilon remain unknown. Recent results indicate signaling from cAMP to PKC. A mechanism connecting cAMP and PKC, two ubiquitous, commonly considered separate pathways, remains elusive. We found that, in cultured DRG neurons, signaling from cAMP to PKCepsilon is not mediated by PKA but by the recently identified cAMP-activated guanine exchange factor Epac. Epac, in turn, was upstream of phospholipase C (PLC) and PLD, both of which were necessary for translocation and activation of PKCepsilon. This signaling pathway was specific to isolectin B4-positive [IB4(+)] nociceptors. Also, in a behavioral model, cAMP produced mechanical hyperalgesia (tenderness) through Epac, PLC/PLD, and PKCepsilon. By delineating this signaling pathway, we provide a mechanism for cAMP-to-PKC signaling, give proof of principle that the mitogen-activated protein kinase pathway-activating protein Epac also stimulates PKC, describe the first physiological function unique for the IB4(+) subpopulation of sensory neurons, and find proof of principle that G-protein-coupled receptors can activate PKC not only through the G-proteins alpha(q) and betagamma but also through alpha(s).
Figures





Comment in
-
An Epac-dependent pain pathway.J Neurosci. 2005 Sep 7;25(36):8113-4. doi: 10.1523/JNEUROSCI.3044-05.2005. J Neurosci. 2005. PMID: 16148218 Free PMC article. Review. No abstract available.
Similar articles
-
Estrogen controls PKCepsilon-dependent mechanical hyperalgesia through direct action on nociceptive neurons.Eur J Neurosci. 2006 Jul;24(2):527-34. doi: 10.1111/j.1460-9568.2006.04913.x. Epub 2006 Jul 12. Eur J Neurosci. 2006. PMID: 16836642
-
EXPRESS: F-actin links Epac-PKC signaling to purinergic P2X3 receptors sensitization in dorsal root ganglia following inflammation.Mol Pain. 2016 Jul 5;12:1744806916660557. doi: 10.1177/1744806916660557. Print 2016. Mol Pain. 2016. PMID: 27385722 Free PMC article.
-
Epac-protein kinase C alpha signaling in purinergic P2X3R-mediated hyperalgesia after inflammation.Pain. 2016 Jul;157(7):1541-1550. doi: 10.1097/j.pain.0000000000000547. Pain. 2016. PMID: 26963850 Free PMC article.
-
Repercussion of cAMP and EPAC in Memory and Signaling.Drug Res (Stuttg). 2022 Feb;72(2):65-71. doi: 10.1055/a-1657-2464. Epub 2022 Jan 3. Drug Res (Stuttg). 2022. PMID: 34979574 Review.
-
Epac and Nociceptor Sensitization.Mol Pain. 2017 Jan-Dec;13:1744806917716234. doi: 10.1177/1744806917716234. Mol Pain. 2017. PMID: 28580839 Free PMC article. Review.
Cited by
-
Threshold-free population analysis identifies larger DRG neurons to respond stronger to NGF stimulation.PLoS One. 2012;7(3):e34257. doi: 10.1371/journal.pone.0034257. Epub 2012 Mar 27. PLoS One. 2012. PMID: 22479579 Free PMC article.
-
Epac stimulation induces rapid increases in connexin43 phosphorylation and function without preconditioning effect.Pflugers Arch. 2010 Sep;460(4):731-41. doi: 10.1007/s00424-010-0854-9. Epub 2010 Jun 29. Pflugers Arch. 2010. PMID: 20585956
-
Methylglyoxal and a spinal TRPA1-AC1-Epac cascade facilitate pain in the db/db mouse model of type 2 diabetes.Neurobiol Dis. 2019 Jul;127:76-86. doi: 10.1016/j.nbd.2019.02.019. Epub 2019 Feb 23. Neurobiol Dis. 2019. PMID: 30807826 Free PMC article.
-
Epac mediates PACAP-dependent long-term depression in the hippocampus.J Physiol. 2009 Jan 15;587(1):101-13. doi: 10.1113/jphysiol.2008.157461. Epub 2008 Nov 10. J Physiol. 2009. PMID: 19001039 Free PMC article.
-
Capturing adenylyl cyclases as potential drug targets.Nat Rev Drug Discov. 2009 Apr;8(4):321-35. doi: 10.1038/nrd2827. Nat Rev Drug Discov. 2009. PMID: 19337273 Review.
References
-
- Bond RA, Leff P, Johnson TD, Milano CA, Rockman HA, McMinn TR, Apparsundaram S, Hyek MF, Kenakin TP, Allen LF, Lefkowitz RJ (1995) Physiological effects of inverse agonists in transgenic mice with myocardial overexpression of the beta 2-adrenoceptor. Nature 374: 272-276. - PubMed
-
- Bos JL, de Bruyn K, Enserink J, Kuiperij B, Rangarajan S, Rehmann H, Riedl J, de Rooij J, van Mansfeld F, Zwartkruis F (2003) The role of Rap1 in integrin-mediated cell adhesion. Biochem Soc Trans 31: 83-86. - PubMed
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical