HDAC4 is required for inflammation-associated thermal hypersensitivity
| Autor: | Crow, Megan, Khovanov, Nikita, Kelleher, Jayne H., Sharma, Simone, Grant, Andrew D., Bogdanov, Yury, Wood, John N., McMahon, Stephen B., Denk, Franziska |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Calcitonin
Inflammation Mice Knockout Nociception epigenetics Sensory Receptor Cells Transcription Genetic Calcitonin Gene-Related Peptide Freund's Adjuvant Down-Regulation Pain TRPV Cation Channels nerve growth factor Histone Deacetylases Mice Inbred C57BL Research Communication Mice Hyperalgesia Hypersensitivity Animals Capsaicin Protein Precursors transcription |
| Zdroj: | Crow, M, Khovanov, N, Kelleher, J H, Sharma, S, Grant, A D, Bogdanov, Y, Wood, J N, McMahon, S B & Denk, F 2015, ' HDAC4 is required for inflammation-associated thermal hypersensitivity ', Faseb Journal, vol. 29, no. 8, pp. 3370-3378 . https://doi.org/10.1096/fj.14-264440 The FASEB Journal |
| DOI: | 10.1096/fj.14-264440 |
| Popis: | Transcriptional alterations are characteristic of persistent pain states, but the key regulators remain elusive. HDAC4 is a transcriptional corepressor that has been linked to synaptic plasticity and neuronal excitability, mechanisms that may be involved in peripheral and central sensitization. Using a conditional knockout (cKO) strategy in mice, we sought to determine whether the loss of HDAC4 would have implications for sensory neuron transcription and nociception. HDAC4 was found to be largely unnecessary for transcriptional regulation of naïve sensory neurons but was essential for appropriate transcriptional responses after injury, with Calca and Trpv1 expression consistently down-regulated in HDAC4 cKO compared to levels in the littermate controls (0.2-0.44-fold change, n = 4 in 2 separate experiments). This down-regulation corresponded to reduced sensitivity to 100 nM capsaicin in vitro (IC50 = 230 ± 20 nM, 76 ± 4.4% wild-type capsaicin responders vs. 56.9 ± 4.7% HDAC4 cKO responders) and to reduced thermal hypersensitivity in the complete Freund's adjuvant (CFA) model of inflammatory pain (1.3-1.4-fold improvement over wild-type controls; n = 5-12, in 2 separate experiments). These data indicate that HDAC4 is a novel inflammatory pain mediator and may be a good therapeutic target, capable of orchestrating the regulation of multiple downstream effectors.-Crow, M., Khovanov, N., Kelleher, J. H., Sharma, S., Grant, A. D., Bogdanov, Y., Wood, J. N., McMahon, S. B., Denk, F. HDAC4 is required for inflammation-associated thermal hypersensitivity. |
| Databáze: | OpenAIRE |
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