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[PMID]: | 28346321 |
[Au] Autor: | Lai CY; Hsieh MC; Ho YC; Lee AS; Wang HH; Cheng JK; Chau YP; Peng HY |
[Ad] Endereço: | From the Department of Veterinary Medicine, College of Veterinary Medicine, National Chung-Hsing University, Taichung, Taiwan (C.-Y.L.); Department of Medicine, Mackay Medical College, New Taipei, Taiwan (C.-Y.L., M.-C.H., Y.-C.H., A.-S.L., H.-H.W., J.-K.C., Y.-P.C., H.-Y.P.); Department of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan (M.-C.H.); and Department of Anesthesiology, Mackay Memorial Hospital, Taipei, Taiwan (J.-K.C.). |
[Ti] Título: | Growth Arrest and DNA-damage-inducible Protein 45ß-mediated DNA Demethylation of Voltage-dependent T-type Calcium Channel 3.2 Subunit Enhances Neuropathic Allodynia after Nerve Injury in Rats. |
[So] Source: | Anesthesiology;126(6):1077-1095, 2017 Jun. | [Is] ISSN: | 1528-1175 |
[Cp] País de publicação: | United States |
[La] Idioma: | eng |
[Ab] Resumo: | BACKGROUND: Growth arrest and DNA-damage-inducible protein 45ß reactivates methylation-silenced neural plasticity-associated genes through DNA demethylation. However, growth arrest and DNA-damage-inducible protein 45ß-dependent demethylation contributes to neuropathic allodynia-associated spinal plasticity remains unclear. METHODS: Adult male Sprague-Dawley rats (654 out of 659) received a spinal nerve ligation or a sham operation with or without intrathecal application of one of the following: growth arrest and DNA-damage-inducible protein 45ß messenger RNA-targeted small interfering RNA, lentiviral vector expressing growth arrest and DNA-damage-inducible protein 45ß, Ro 25-6981 (an NR2B-bearing N-methyl-D-aspartate receptor antagonist), or KN-93 (a calmodulin-dependent protein kinase II antagonist) were used for behavioral measurements, Western blotting, immunofluorescence, dot blots, detection of unmodified cytosine enrichment at cytosine-phosphate-guanine site, chromatin immunoprecipitation quantitative polymerase chain reaction analysis, and slice recordings. RESULTS: Nerve ligation-enhanced growth arrest and DNA-damage-inducible protein 45ß expression (n = 6) in ipsilateral dorsal horn neurons accompanied with behavioral allodynia (n = 7). Focal knockdown of growth arrest and DNA-damage-inducible protein 45ß expression attenuated ligation-induced allodynia (n = 7) by reducing the binding of growth arrest and DNA-damage-inducible protein 45ß to the voltage-dependent T-type calcium channel 3.2 subunit promoter (n = 6) that decreased expression of and current mediated by the voltage-dependent T-type calcium channel 3.2 subunit (both n = 6). In addition, NR2B-bearing N-methyl-D-aspartate receptors and calmodulin-dependent protein kinase II act in an upstream cascade to increase growth arrest and DNA-damage-inducible protein 45ß expression, hence enhancing demethylation at the voltage-dependent T-type calcium channel 3.2 subunit promoter and up-regulating voltage-dependent T-type calcium channel 3.2 subunit expression. Intrathecal administration of Ro 25-6981, KN-93, or a growth arrest and DNA-damage-inducible protein 45ß-targeting small interfering RNA (n = 6) reversed the ligation-induced enrichment of unmodified cytosine at the voltage-dependent T-type calcium channel 3.2 subunit promoter by increasing the associated 5-formylcytosine and 5-carboxylcytosine levels. CONCLUSIONS: By converting 5-formylcytosine or 5-carboxylcytosine to unmodified cytosine, the NR2B-bearing N-methyl-D-aspartate receptor, calmodulin-dependent protein kinase II, or growth arrest and DNA-damage-inducible protein 45ß pathway facilitates voltage-dependent T-type calcium channel 3.2 subunit gene demethylation to mediate neuropathic allodynia. |
[Mh] Termos MeSH primário: |
Antígenos de Diferenciação/metabolismo Canais de Cálcio Tipo T/metabolismo Metilação de DNA Hiperalgesia/metabolismo Neuralgia/metabolismo Nervos Espinhais/lesões
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[Mh] Termos MeSH secundário: |
Animais Antígenos de Diferenciação/genética Western Blotting Canais de Cálcio Tipo T/genética Modelos Animais de Doenças Imunofluorescência Hiperalgesia/genética Masculino Neuralgia/genética Reação em Cadeia da Polimerase Ratos Ratos Sprague-Dawley Nervos Espinhais/metabolismo
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[Pt] Tipo de publicação: | JOURNAL ARTICLE |
[Nm] Nome de substância:
| 0 (Antigens, Differentiation); 0 (Calcium Channels, T-Type); 0 (Gadd45b protein, rat) |
[Em] Mês de entrada: | 1707 |
[Cu] Atualização por classe: | 170731 |
[Lr] Data última revisão:
| 170731 |
[Sb] Subgrupo de revista: | AIM; IM |
[Da] Data de entrada para processamento: | 170328 |
[St] Status: | MEDLINE |
[do] DOI: | 10.1097/ALN.0000000000001610 |
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