Epac-protein kinase C alpha signaling in purinergic P2X3R-mediated hyperalgesia after inflammation

Yanping Gu, Guangwen Li, Yong Chen, Li-Yen Huang

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

Sensitization of purinergic P2X3 receptors (P2X3Rs) is a major mechanism contributing to injury-induced exaggerated pain responses. We showed in a previous study that cyclic adenosine monophosphate (cAMP)-dependent guanine nucleotide exchange factor 1 (Epac1) in rat sensory dorsal root ganglia (DRGs) is upregulated after inflammatory injury, and it plays a critical role in P2X3R sensitization by activating protein kinase C epsilon (PKCϵ) inside the cells. protein kinase C epsilon has been established as the major PKC isoform mediating injury-induced hyperalgesic responses. On the other hand, the role of PKCα in receptor sensitization was seldom considered. Here, we studied the participation of PKCα in Epac signaling in P2X3R-mediated hyperalgesia. The expression of both Epac1 and Epac2 and the level of cAMP in DRGs are greatly enhanced after complete Freund adjuvant (CFA)-induced inflammation. The expression of phosphorylated PKCα is also upregulated. Complete Freund adjuvant (CFA)-induced P2X3R-mediated hyperalgesia is not only blocked by Epac antagonists but also by the classical PKC isoform inhibitors, Go6976, and PKCα-siRNA. These CFA effects are mimicked by the application of the Epac agonist, 8-(4-chlorophenylthio)-2 -O-methyl-cAMP (CPT), in control rats, further confirming the involvement of Epacs. Because the application of Go6976 prior to CPT still reduces CPT-induced hyperalgesia, PKCα is downstream of Epacs to mediate the enhancement of P2X3R responses in DRGs. The pattern of translocation of PKCα inside DRG neurons in response to CPT or CFA stimulation is distinct from that of PKCϵ. Thus, in contrast to prevalent view, PKCα also plays an essential role in producing complex inflammation-induced receptor-mediated hyperalgesia.

Original languageEnglish (US)
Pages (from-to)1541-1550
Number of pages10
JournalPain
Volume157
Issue number7
DOIs
StatePublished - Jul 1 2016

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Keywords

  • DRG
  • Epac1
  • Epac2
  • inflammatory pain
  • P2X3R
  • PKCα
  • PKCϵ

ASJC Scopus subject areas

  • Clinical Neurology
  • Anesthesiology and Pain Medicine
  • Neurology
  • Pharmacology

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