In:
The Journal of Neuroscience, Society for Neuroscience, Vol. 30, No. 38 ( 2010-09-22), p. 12806-12815
Abstract:
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 E 2 (PGE 2 )-induced hyperalgesia is prolonged from 〈 6 h in wild-type (WT) mice to 3 d in mice with low GRK2 in Na v 1.8 + nociceptors ( SNS–GRK2 +/− mice). This prolongation of PGE 2 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. PGE 2 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 PGE 2 , 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.
Type of Medium:
Online Resource
ISSN:
0270-6474
,
1529-2401
DOI:
10.1523/JNEUROSCI.3142-10.2010
Language:
English
Publisher:
Society for Neuroscience
Publication Date:
2010
detail.hit.zdb_id:
1475274-8
SSG:
12
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