Neurotrophin Activation of Nfat-dependent Transcription Contributes to the Regulation of Pro-nociceptive Genes.
From: Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Journal of neurochemistry
- Publish Date: Aug 2007
- ISSN: 0022-3042
- Volume: 102
- Issue: 4
- Pages: 1162-74
- Medium: Print
- Language: English
- Citation (JAMA): Groth Rachel D, Coicou Lia G, Mermelstein Paul G, et al. Neurotrophin Activation of Nfat-dependent Transcription Contributes to the Regulation of Pro-nociceptive Genes.. J. Neurochem. Aug 2007;102:1162-74
Abstract
Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) play key roles in the development of inflammation-induced hyperalgesia by triggering the expression of pro-nociceptive genes within primary afferent and spinal neurons. However, the mechanisms by which neurotrophins elicit gene expression remain largely unknown. Recently, neurotrophins have been shown to activate members of the calcineurin (CaN)-regulated, nuclear factor of activated T-cells (NFATc) family of transcription factors within brain. Thus, we hypothesized that NFATc transcription factors couple neurotrophin signaling to gene expression within primary afferent and spinal neurons. In situ hybridization revealed NFATc4 mRNA within the dorsal root ganglion and spinal cord. In cultured dorsal root ganglion cells, NGF triggered NFAT-dependent transcription in a CaN-sensitive manner. Further, increased BDNF expression following NGF treatment relied on CaN, thereby suggesting that NGF regulates BDNF transcription via activation of NFATc4. Within cultured spinal cells, BDNF also activated CaN-dependent, NFAT-regulated gene expression. Interestingly, BDNF stimulation increased the expression of the pro-nociceptive genes cyclooxygenase-2, neurokinin-1 receptor, inositol trisphosphates receptor type 1, and BDNF itself, through both NFAT-dependent and NFAT-independent transcriptional mechanisms. Our results suggest that regulation of pro-nociceptive genes through activation of NFAT-dependent transcription is one mechanism by which NGF and BDNF signaling contributes to the development of persistent pain states.
Mesh Headings (Keywords): Animals, Brain-Derived Neurotrophic Factor, Calcineurin, Cells, Cultured, Drug Interactions, Female, Ganglia, Spinal, Humans, Immunosuppressive Agents, In Situ Hybridization, Mice, Mice, Inbred C3H, NFATC Transcription Factors, Nerve Growth Factor, Nerve Growth Factors, Neurons, Pregnancy, Rats, Rats, Sprague-Dawley, Tacrolimus, Transcription, Genetic
Check for Full Text / PubMed Unique Identifier (PMID): 17488277
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