Low nociceptor GRK2 prolongs prostaglandin E2 hyperalgesia via biased cAMP signaling to Epac/Rap1, protein kinase Cepsilon, and MEK/ERK.
Hyperexcitability of peripheral nociceptive pathways is often associated with inflammation and is an important mechanism underlying inflammatory pain. Here we describe a completely novel mechanism via which nociceptor G-protein-coupled receptor kinase 2 (GRK2) contributes to regulation of inflammatory hyperalgesia. We show that nociceptor GRK2 is downregulated during inflammation. In addition, ... we show for the first time that prostaglandin E2 (PGE2)-induced hyperalgesia is prolonged from <6 h in wild-type (WT) mice to 3 d in mice with low GRK2 in Nav1.8+ nociceptors (SNS-GRK2+/- mice). This prolongation of PGE2 hyperalgesia in SNS-GRK2+/- mice does not depend on changes in the sensitivity of the prostaglandin receptors because prolonged hyperalgesia also developed in response to 8-Br-cAMP. PGE2 or cAMP-induced hyperalgesia in WT mice is PKA dependent. However, PKA activity is not required for hyperalgesia in SNS-GRK2+/- mice. SNS-GRK2+/- mice developed prolonged hyperalgesia in response to the Exchange proteins directly activated by cAMP (Epac) activator 8-pCPT-2'-O-Me-cAMP (8-pCPT). Coimmunoprecipitation experiments showed that GRK2 binds to Epac1. In vitro, GRK2 deficiency increased 8-pCPT-induced activation of the downstream effector of Epac, Rap1, and extracellular signal-regulated kinase (ERK). In vivo, inhibition of MEK1 or PKCε prevented prolonged PGE2, 8-Br-cAMP, and 8-pCPT hyperalgesia in SNS-GRK2+/- mice. In conclusion, we discovered GRK2 as a novel Epac1-interacting protein. A reduction in the cellular level of GRK2 enhances activation of the Epac-Rap1 pathway. In vivo, low nociceptor GRK2 leads to prolonged inflammatory hyperalgesia via biased cAMP signaling from PKA to Epac-Rap1, ERK/PKCε pathways.
Mesh Terms:
Animals, Blotting, Western, Cell Line, Cells, Cultured, Cyclic AMP, Dinoprostone, Down-Regulation, Female, G-Protein-Coupled Receptor Kinase 2, Ganglia, Spinal, Guanine Nucleotide Exchange Factors, Humans, Hyperalgesia, Immunoprecipitation, Inflammation, Mice, Mice, Transgenic, Mitogen-Activated Protein Kinases, Protein Kinase C-epsilon, Signal Transduction, rap1 GTP-Binding Proteins
Animals, Blotting, Western, Cell Line, Cells, Cultured, Cyclic AMP, Dinoprostone, Down-Regulation, Female, G-Protein-Coupled Receptor Kinase 2, Ganglia, Spinal, Guanine Nucleotide Exchange Factors, Humans, Hyperalgesia, Immunoprecipitation, Inflammation, Mice, Mice, Transgenic, Mitogen-Activated Protein Kinases, Protein Kinase C-epsilon, Signal Transduction, rap1 GTP-Binding Proteins
J. Neurosci.
Date: Sep. 22, 2010
PubMed ID: 20861385
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