帕金森氏症已知是一種運動障礙疾病，而這個疾病的發生是由於大腦黑質區的多巴胺神經元缺失和位於紋狀體的多巴胺神經末梢退化，使多巴胺分泌不足所導致的。Kv2.1為延遲整流鉀離子通道，主要功能藉由調控神經興奮、動作電位和強直放電。然而延遲整流鉀離子電流在帕金森氏症所導致黑質紋狀體退化中扮演的角色仍然是不確定的。在本篇研究中，我們發現當使用亞慢性MPTP處理時，電位敏感的鉀離子通道Kv2.1的表現量增加，並觀察到黑質區和紋狀體的電位敏感的鉀離子通道有擴散的現象。接下來我們想知道電位敏感的鉀離子通道Kv2.1的增加是否對MPTP所導致的多巴胺神經元退化有關連性，因此我們對進行亞慢性MPTP毒性的老鼠使用前處理和後處理電位敏感的鉀離子通道Kv2.1的抑制劑GxTx，發現在多巴胺神經元和其神經末梢起了保護的作用，意味著抑制電位敏感的鉀離子通道Kv2.1可以保護多巴胺神經免受MPTP的毒性傷害。另外在離體實驗，我們給予MPP+48小時給藥增加電位敏感的鉀離子通道Kv2.1之表現量，改變了通道分布情形，並且促使細胞凋亡的鉀電流增加在巴胺神經母細胞株MN9D細胞株中，並且在加入其抑制劑GxTx後抑制了MPP+的毒性傷害。綜合我們的研究結果，我們發現MPTP/MPP+增加了電位敏感的鉀離子通道Kv2.1表現量並且改變了其位置，促使黑質紋狀體的多巴胺神經元和其神經末梢退化。相反地，當抑制電位敏感的鉀離子通道Kv2.1時可以保護多巴胺神經免受MPTP的毒性傷害。而其中的機制是由於MPTP/MPP+增加了電位敏感的鉀離子通道Kv2.1表現量並且改變了其位置，關係到腺苷單磷酸活化蛋白激酶AMPK的磷酸化和剪切酶cleave caspase 3 的增加，促使氧化壓力增加和能量的減少，缺少能量時進而活化AMPK來調控電位敏感的鉀離子通道Kv2.1而導致細胞凋亡。更重要的是藉由Kv2.1的抑制劑GxTx可以降低多巴胺神經元和其神經末梢的受損，保護多巴胺神經免受MPTP的毒性所導致黑質區和紋狀體的神經退化。

Parkinson’s disease which is known as the movement disorder because of loss of dopaminergic neurons (DAnergic neurons) in the substantia nigra pars compacta (SNpc) and degeneration of DAnergic terminals in the dorsal striatum. Kv2.1 is a predominant delayed rectifier K+ current that regulates neuronal excitability, action potential duration, and tonic spiking. The mechanism underlying a delayed rectifier K+ current in the degeneration of nigrostriatal degeneration of Parkinson’s disease remains uncertain. Here, we show that subchronic MPTP treatment increases channel expression and diffusion of Kv2.1. Next, to understand whether this increase of Kv2.1 channel is necessary for MPTP-induced nigorstriatal degeneration, mice pre or post-treated with Kv2.1 blocker (Guangxitoxin 1E, GxTx) following by subchronic MPTP regimen showed protective effects on SNpc DA neurons and DAnergic axon terminal in the STR, suggesting that inhibition of Kv2.1 channel protects DA neurons from MPTP toxicity. In vitro, effects of forty-eight hours of MPP+ treatment were shown that an increase in expression of Kv2.1 channel, altered distribution and induced apoptotic potassium conductance in the MN9D cells and GxTx pretreatment inhibited these effects of MPP+. In summary, MPTP/MPP+ increased expression and localization of Kv2.1 channel to promote nigrostriatal degeneration. Conversely, inhibition of Kv2.1 channel protects DA neurons in the SNpc and DAnergic terminals in the STR from MPTP insult. This mechanism underlying in which MPTP/MPP+ increased Kv2.1 channel expression and localization are correlated with AMPK phosphorylation and cleave caspase 3 elevation, which further support that oxidative stress and energy deprivation activated AMPK modify Kv2.1 channels to induce cell apoptosis. Most importantly, inhibition of Kv2.1 channels with specific blocker GxTx provide protects nigrostriatal degeneration in the subchronic MPTP mouse model.

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