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Targeted disruption of Kv2.1-VAPA association provides neuroprotection against ischemic stroke in mice by declustering Kv2.1 channels.
Science Advances ( IF 11.7 ) Pub Date : 2020-07-01 , DOI: 10.1126/sciadv.aaz8110
Anthony J Schulien 1, 2 , Chung-Yang Yeh 1, 2 , Bailey N Orange 1, 2 , Olivia J Pav 1, 2 , Madelynn P Hopkins 1, 2 , Aubin Moutal 3 , Rajesh Khanna 3 , Dandan Sun 2, 4 , Jason A Justice 1, 2 , Elias Aizenman 1, 2
Affiliation  

Kv2.1 channels mediate cell death–enabling loss of cytosolic potassium in neurons following plasma membrane insertion at somatodendritic clusters. Overexpression of the carboxyl terminus (CT) of the cognate channel Kv2.2 is neuroprotective by disrupting Kv2.1 surface clusters. Here, we define a seven–amino acid declustering domain within Kv2.2 CT (DP-2) and demonstrate its neuroprotective efficacy in a murine ischemia-reperfusion model. TAT-DP-2, a membrane-permeable derivative, induces Kv2.1 surface cluster dispersal, prevents post-injurious pro-apoptotic potassium current enhancement, and is neuroprotective in vitro by disrupting the association of Kv2.1 with VAPA. TAT-DP-2 also induces Kv2.1 cluster dispersal in vivo in mice, reducing infarct size and improving long-term neurological function following stroke. We suggest that TAT-DP-2 induces Kv2.1 declustering by disrupting Kv2.1-VAPA association and scaffolding sites required for the membrane insertion of Kv2.1 channels following injury. We present the first evidence of targeted disruption of Kv2.1-VAPA association as a neuroprotective strategy following brain ischemia.



中文翻译:


靶向破坏 Kv2.1-VAPA 关联可通过分散 Kv2.1 通道为小鼠提供针对缺血性中风的神经保护。



Kv2.1 通道介导细胞死亡,使质膜插入体细胞树突簇后神经元中胞质钾的损失。同源通道 Kv2.2 羧基末端 (CT) 的过度表达通过破坏 Kv2.1 表面簇来发挥神经保护作用。在这里,我们在 Kv2.2 CT (DP-2) 中定义了一个七氨基酸去簇结构域,并在小鼠缺血再灌注模型中证明了其神经保护功效。 TAT-DP-2 是一种膜渗透性衍生物,可诱导 Kv2.1 表面簇分散,防止损伤后促凋亡钾电流增强,并通过破坏 Kv2.1 与 VAPA 的关联来发挥体外神经保护作用。 TAT-DP-2 还在小鼠体内诱导 Kv2.1 簇分散,减少梗塞面积并改善中风后的长期神经功能。我们认为 TAT-DP-2 通过破坏 Kv2.1-VAPA 关联和损伤后 Kv2.1 通道膜插入所需的支架位点来诱导 Kv2.1 去簇。我们提出了第一个证据,表明有针对性地破坏 Kv2.1-VAPA 关联作为脑缺血后的神经保护策略。

更新日期:2020-07-01
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