Down-regulation of miR-3068-3p enhances kcnip4-regulated A-type potassium current to protect against glutamate-induced excitotoxicity.
J Neurochem
; 153(5): 617-630, 2020 06.
Article
em En
| MEDLINE
| ID: mdl-31792968
The main cause of excitotoxic neuronal death in ischemic stroke is the massive release of glutamate. Recently, microRNAs (miRNAs) have been found to play an essential role in stroke pathology, although the molecular mechanisms remain to be investigated. Here, to identify potential candidate miRNAs involved in excitotoxicity, we treated rat primary cortical neurons with glutamate and found that miR-3068-3p, a novel miRNA, was up-regulated. We hypothesized that restoring miR-3068-3p expression might influence the neuronal injury outcomes. The inhibition of miR-3068-3p, using tough decoy lentiviruses, significantly attenuated the effects of glutamate on neuronal viability and intracellular calcium overload. To unravel the mechanisms, we employed bioinformatics analysis and RNA sequencing to identify downstream target genes. Additional luciferase assays and western blots validated kcnip4, a Kv4-mediated A-type potassium current (IA ) regulator, as a direct target of miR-3068-3p. The inhibition of miR-3068-3p increased kcnip4 expression and vice versa. In addition, the knockdown of kcnip4 by shRNA abolished the protective effect of miR-3068-3p, and over-expressing kcnip4 alone was sufficient to play a neuroprotective role in excitotoxicity. Moreover the inhibition of miR-3068-3p enhanced the IA density, and the pharmacological inhibition of IA abrogated the protective role of miR-3068-3p inhibition and kcnip4 over-expression. Therefore, we conclude that inhibition of miR-3068-3p protects against excitotoxicity via its target gene, kcnip4, and kcnip4-regulated IA . Our data suggest that the miR-3068-3p/kcnip4 axis may serve as a novel target for the treatment of ischemic stroke.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Regulação para Baixo
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Ácido Glutâmico
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MicroRNAs
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Proteínas Interatuantes com Canais de Kv
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Neuroproteção
Limite:
Animals
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Female
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Humans
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Pregnancy
Idioma:
En
Revista:
J Neurochem
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
China