Journal
MOLECULAR AND CELLULAR NEUROSCIENCE
Volume 37, Issue 1, Pages 170-177Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.mcn.2007.09.004
Keywords
chemokine receptors; dorsal root ganglion; neuropathic pain; NFAT; calcineurin; FK506; cyclosporin A
Categories
Funding
- NIDA NIH HHS [R01 DA013141-04, R01 DA013141, R01 DA013141-05, R01 DA013141-08S1, R01 DA013141-02, R01 DA013141-06A2, R01 DA013141-07, DA013141, R01 DA013141-01, R01 DA013141-08, R01 DA013141-03] Funding Source: Medline
- NIMH NIH HHS [MH040165, R37 MH040165] Funding Source: Medline
- NINDS NIH HHS [R01 NS043095-05, R01 NS043095-06A2, R01 NS043095-02, R01 NS043095, NS043095, R01 NS043095-03, R01 NS043095-04, R01 NS043095-01A1] Funding Source: Medline
- NATIONAL INSTITUTE OF MENTAL HEALTH [R01MH040165, R37MH040165] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS043095] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON DRUG ABUSE [R01DA013141] Funding Source: NIH RePORTER
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Upregulation of CCR2 chemokine receptor expression by dorsal root ganglion (DRG) neurons is an important process in the development and maintenance of neuropathic pain. CCR2 is not expressed by DRG neurons under normal conditions but is upregulated in several animal models of neuropathic pain where its signaling is excitatory. However, the molecular mechanisms underlying neuronal upregulation of CCR2 have not been investigated. We examined the promoter region of the CCR2 gene and found that a binding site for the nuclear factor of activated T-cells (NFAT) was conserved among species. The NFAT element was functional since the CCR2 promoter was activated by a constitutively active form of calcineurin A, whereas a point mutation in the NFAT binding site abrogated it. Activation of the NFAT pathway in the DRG neuronal cell line 1711 increased CCR2 promoter activity and induced CCR2 transcription. Moreover, depolarization of cultured DRG neurons induced de novo synthesis of CCR2 mRNA, which was blocked by the calcineurin inhibitors cyclosporin A and FK506. These data indicate that CCR2 is a target of the NFAT pathway and suggest that tonic excitation of DRG neurons in association with chronic pain may lead to neuronal CCR2 upregulation via activation of the NFAT pathway. (C) 2007 Elsevier Inc. All rights reserved.
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