Title |
Transcriptional Regulation of Metabotropic Glutamate Receptor 2/3 Expression by the NF-κB Pathway in Primary Dorsal Root Ganglia Neurons: A Possible Mechanism for the Analgesic Effect of L-Acetylcarnitine
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Published in |
Molecular Pain, June 2006
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DOI | 10.1186/1744-8069-2-20 |
Pubmed ID | |
Authors |
Santina Chiechio, Agata Copani, Laura De Petris, Maria Elena P Morales, Ferdinando Nicoletti, Robert W Gereau |
Abstract |
L-acetylcarnitine (LAC), a drug utilized for the treatment of neuropathic pain in humans, has been shown to induce analgesia in rodents by up-regulating the expression of metabotropic glutamate receptor 2 (mGlu2) in dorsal root ganglia (DRG). We now report that LAC-induced upregulation of mGlu2 expression in DRG cultures involves transcriptional activation mediated by nuclear factor-kappaB (NF-kappaB). A single application of LAC (250 muM) to DRG cultures induced a transient increase in mGlu2 mRNA, which was observable after 1 hour and was no longer detectable after 1 to 4 days. In contrast, LAC treatment had no effect on mGlu3 mRNA expression. Pharmacological inhibition of NF-kappaB binding to DNA by caffeic acid phenethyl ester (CAPE) (2.5 microg/ml for 30 minutes) reduced the constitutive expression of mGlu2 and mGlu3 mRNA after 1-4 days and reduced the constitutive expression of mGlu2/3 protein at 4 days. This evidence combined with the expression of p65/RelA and c-Rel in DRG neurons indicated that expression of mGlu2 and mGlu3 is endogenously regulated by the NF-kappaB family of transcription factors. Consistent with this idea, the transient increase in mGlu2 mRNA induced by LAC after 1 hour was completely suppressed by CAPE. Furthermore, LAC induced an increase in the acetylation of p65/RelA, a process that enhances the transcriptional activity of p65/RelA. These results are consistent with the hypothesis that LAC selectively induces the expression of mGlu2 by acting as a donor of acetyl groups, thus enhancing the activity of the NF-kappaB family of transcription factors. Accordingly, we show that carnitine, which has no effect on pain thresholds, had no effect on p65/RelA acetylation and did not enhance mGlu2 expression. Taken together, these results demonstrate that expression of mGlu2 and mGlu3 mRNA is regulated by the NF-kappaB transcriptional machinery, and that agents that increase acetylation and activation of NF-kappaB transcription factors might induce analgesia via upregulation of mGlu2 in DRG neurons. |
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Geographical breakdown
Country | Count | As % |
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Italy | 2 | 4% |
Unknown | 51 | 91% |
Demographic breakdown
Readers by professional status | Count | As % |
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Researcher | 9 | 16% |
Other | 6 | 11% |
Student > Master | 5 | 9% |
Student > Doctoral Student | 4 | 7% |
Other | 10 | 18% |
Unknown | 11 | 20% |
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Pharmacology, Toxicology and Pharmaceutical Science | 3 | 5% |
Other | 2 | 4% |
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