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標題: | 視丘下核神經元上T型鈣離子通道之門閥開關及藥理性質 Gating Properties and Pharmacological Modulation of T-type Calcium Channels in Subthalamic Nucleus Neurons. |
作者: | Yu-Fang Chien 簡郁芳 |
指導教授: | 郭鐘金 |
關鍵字: | 視丘下核,T型鈣離子通道,鎳離子,巴金森氏症, Subthalamic nucleus,T-type calcium channel,Nickel,Mibefradil, |
出版年 : | 2011 |
學位: | 碩士 |
摘要: | 視丘下核在生物的運動行為控制上扮演著非常關鍵的角色。低電壓活化的鈣離子通道,也叫做T型鈣離子通道,被認為和神經元震盪放電的調節有著重要的關聯,因此這個通道活性的改變,有可能和一些動作障礙疾病,例如:巴金森氏症之發生有關係。
在這裡我們利用了全細胞膜片箝制術來研究視丘下核單一神經元的低電壓活化鈣離子通道之生物物理特性。在低電壓活化鈣離子通道的門閥性質中我們發現其去活化速率具有電壓依賴性,而在不活化速率及由不活化態回復的速率則僅有部分之電壓依賴性,也就是在超過特定電壓範圍時其速率有飽和的現象產生(分別在-40mV以上及-110mV以下電壓範圍可見飽和)。與視丘神經元的T型鈣離子通道比較之下,視丘下核神經元於平衡狀態下通道的開啟比例較視丘神經原來的高,這可能提供了視丘下核神經元於自發性放電中有較好的效率。我們同時研究了對低電壓活化鈣離子通道具選擇敏感性的二價鎳離子的作用。我們發現其在高鈣離子濃度溶液(10 mM)中較低鈣溶液(2mM)有較高之IC50數值(各為166.2μM及58.2μM),暗示著胞外之鈣離子對於鎳離子在通道的抑制作用可能具有競爭關係。根據上述我們及前人的實驗數據,鎳的可能作用機轉有兩個:(1)單純的阻斷T型鈣離子電流(2)影響T型鈣離子通道的活化門閥性質。而後,我們也研究了另一個對T型鈣離子通道具有高度專一性及強度的Mibfradil藥物作用(IC50約為1μM),我們發現在加入這個藥物之後不但增加了T型鈣離子通道不活化態的比例,而且也明顯的減少T型鈣離子通道由不活化態回復的速度,這使得 mibfradil可能降低休息狀態下可用的T型鈣離子通道的數目,而達到抑制神經元過度興奮放電的效果。 The subthalamic nucleus (STN) plays a key role in motor control.Low voltage activated (LVA) Ca2+ currents (or T-type Ca2+ currents) are believed to be important in the regulation of neuronal burst discharge and network oscillations,and thus may play an important role in the pathophysiology of Parkinson’s disease and some other movement disorders.We applied whole cell patch-clamp technique to study the biophysical properties of LVA Ca2+ currents in acutely dissociated neurons from subthalamic nucleus.For the gating properties of LVA , we found that the deactivation rate of LVA are voltage-dependent.On the other hand , the rate of inactivation and recovery from inactivation are also voltage-dependent,but are saturable beyond at voltage -40mV and -110mV,respectively. Compared with the thalamic neurons,LVA Ca2+currents in STN neurons have relative high open probability and thus may better sustain high frequency firings.We also studied the blocking effect of divalent cation Ni2+ which was respected to have relatively selective effect on LVA currents.The half maximal inhibitory concentration( IC50) in high Ca2+ bath solution(10mM) is significantly higher than that in low Ca2+ bath solution(2mM), suggesing that extend Ca2+ competes with Ni2+ for the blocking site on the Ca2+ channel. According our result, Ni2+ may have two possible action on the LVA currents in STN (1)pore blocking effect (2)alter the activation gating behavior of T cuurent.We also investigated the effect of mibfradil,another relatively specific and potent inhibitor of T-type Ca2+ currents.We found that mibfradil not only increases the proportion of inactivated calcium channel ,but also significantly slows the recovery rate from inactivated T-type Ca2+ channels.It is likely that mibfradil reduces the available T-type Ca2+channels,thus may decreasing the possibility of excessive repetitive neuronal discharges. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/23398 |
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