The selective disruption of the JNK2/Syntaxin-1A interaction by JGRi1 protects against NMDA-evoked toxicity in SH-SY5Y cells

IF 4.4 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Neurochemistry international Pub Date : 2024-08-03 DOI:10.1016/j.neuint.2024.105824
M. Cimino , M. Feligioni
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Abstract

N-methyl-D-aspartate (NMDA) receptors are calcium-permeable ion-channel receptors, specifically activated by glutamate, that permit the activation of specific intracellular calcium-dependent pathways. Aberrant NMDA receptor activation leads to a condition known as excitotoxicity, in which excessive calcium inflow induces apoptotic pathways. To date, memantine is the only NMDA receptor antagonist authorized in clinical practice, hence, a better understanding of the NMDA cascade represents a need to discover novel pharmacological targets.

We previously reported non-conventional intracellular signaling triggered by which, upon activation, promotes the interaction between JNK2 and STX1A which enhances the rate of vesicular secretion. We developed a cell-permeable peptide, named JGRi1, able to disrupt such interaction, thus reducing vesicular secretion. In this work, to selectively study the effect of JGRi1 in a much simpler system, we employed neuroblastoma cells, SH-SY5Y. We found that SH-SY5Y cells express the components of the NMDA receptor-JNK2 axis and that the NMDA stimulus increases the rate of vesicle release. Both JGRi1 and memantine protected SH-SY5Y cells from NMDA toxicity, but only JGRi1 reduced the interaction between JNK2 and STX1A. Both drugs successfully reduced NMDA-induced vesicle release, although, unlike memantine, JGRi1 did not prevent calcium influx. NMDA treatment induced JNK2 expression, but not JNK1 or JNK3, which was prevented by both JGRi1 and memantine, suggesting that JNK2 may be specifically involved in the response to NMDA.

In conclusion, being JGRi1 able to protect cells against NMDA toxicity by interfering with JNK2/STX1A interaction, it could be considered a novel pharmacological tool to counteract excitotoxicity.

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JGRi1 对 JNK2/SYNTAXIN-1A 相互作用的选择性分离可保护 SH-SY5Y 细胞免受 NMDA 引起的毒性。
N-甲基-D-天冬氨酸(NMDA)受体是钙离子通道受体,专门由谷氨酸激活,允许激活特定的细胞内钙依赖途径。NMDA 受体的异常激活会导致一种被称为兴奋性中毒的病症,在这种病症中,过量的钙流入会诱导细胞凋亡途径。迄今为止,美金刚是唯一获准用于临床实践的 NMDA 受体拮抗剂,因此需要更好地了解 NMDA 级联,以发现新的药理靶点。我们以前曾报道过由其触发的非常规细胞内信号传导,这种信号传导在激活后会促进 JNK2 和 STX1A 之间的相互作用,从而提高囊泡分泌率。我们开发了一种名为 JGRi1 的细胞渗透性多肽,它能破坏这种相互作用,从而减少囊泡分泌。在这项工作中,为了在一个更简单的系统中选择性地研究 JGRi1 的作用,我们采用了神经母细胞瘤细胞 SH-SY5Y。我们发现,SH-SY5Y 细胞表达 NMDA 受体-JNK2 轴的成分,NMDA 刺激会增加囊泡的释放速度。JGRi1和美金刚都能保护SH-SY5Y细胞免受NMDA的毒性,但只有JGRi1能减少JNK2和STX1A之间的相互作用。两种药物都成功地减少了 NMDA 诱导的囊泡释放,但与美金刚不同的是,JGRi1 不能阻止钙离子流入。NMDA 处理会诱导 JNK2 的表达,但不会诱导 JNK1 或 JNK3 的表达,JGRi1 和美金刚均可阻止这种表达,这表明 JNK2 可能专门参与了对 NMDA 的反应。总之,由于 JGRi1 能够通过干扰 JNK2/STX1A 的相互作用来保护细胞免受 NMDA 的毒性,因此它可被视为一种对抗兴奋性毒性的新型药理学工具。
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来源期刊
Neurochemistry international
Neurochemistry international 医学-神经科学
CiteScore
8.40
自引率
2.40%
发文量
128
审稿时长
37 days
期刊介绍: Neurochemistry International is devoted to the rapid publication of outstanding original articles and timely reviews in neurochemistry. Manuscripts on a broad range of topics will be considered, including molecular and cellular neurochemistry, neuropharmacology and genetic aspects of CNS function, neuroimmunology, metabolism as well as the neurochemistry of neurological and psychiatric disorders of the CNS.
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