HMJ-53A加速Kv通道慢性鈍化之機轉; Mechanisms for the acceleration of Kv channel slow inactivation by HMJ-53A

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题名:	HMJ-53A加速Kv通道慢性鈍化之機轉;Mechanisms for the acceleration of Kv channel slow inactivation by HMJ-53A
作者:	趙家佳;Chia-Chia Chao
贡献者:	中國醫藥大學：醫學研究所
关键词:	電壓調控鉀離子通道;慢性鈍化;電生理;神經細胞;HMJ-53A;Voltage-gated Kv channels;C-type inactivation;Electrophysiology;Nerve cells
日期:	2008-06-23
上传时间:	2009-08-13 14:50:15 (UTC+8)
摘要:	在可興奮性細胞，例如，神經細胞和內分泌細胞，利用電壓調控鉀離子(Kv)通道，使其膜電位於去極化後可復極化。某些Kv通道在去極化之過程中，會表現慢性鈍化之現象，此鈍化作用會使Kv通道產生某種形式的關閉，而其發生是因通道裡離子選擇性過濾器壓縮。至今，尚未有一個針對此慢性鈍化之特異性的探測藥物。我們發現一個新的藥物，HMJ-53A (30 μM)在小鼠神經瘤細胞株 (N2A)上，有選擇性的加速Kv通道之慢性鈍化（沒加與有加HMJ-53A之衰退 τ，分別為1677 ± 120 ms 和 85.6 ± 7.7 ms）。HMJ-53A把Kv通道穩定鈍化曲線左移12mV，且不影響其活化階段。此外，我們在微細玻璃管電極內（細胞內）加入HMJ-53A，並不會產生加速Kv通道之慢性鈍化現象；而從此數據顯示，HMJ-53A作用在細胞外而非細胞內。HMJ-53A阻斷Kv通道上鉀離子外流，而所測得之電流，不需要Kv通道開啟。此外，HMJ-53A之阻斷Kv通道電流及鈍化之時間常數，不會受到去極化程度及細胞內鉀離子濃度的影響。所以，HMJ-53A不會直接堵塞Kv通道之孔洞，而是讓圍著通道孔之選擇性過濾器加快壓縮。綜合以上的結果可以得知，HMJ-53A可有選擇性的加速Kv通道之慢性鈍化，可作為探測Kv通道鈍化閥門之對抗藥。 Voltage-gated K+ (Kv) channels are important in repolarization of excitable cells such as neurons and endocrine cells. Kv channel gating exhibits slow inactivation (slow current decay) during continuous depolarization. The molecular mechanism involved in such slow inactivation is not completely understood, but evidence has suggested that it involves a restriction of the outer channel pore surrounding the selectivity filter. Pharmacological tools probing this slow inactivation process are scarce. In this work we reported that bath application of HMJ-53A (30 μM), a novel compound, could drastically speed up the slow decay (decay τ＝1677±120 ms and 85.6 ±7.7 ms, respectively, in the absence and presence of HMJ-53A) of Kv currents in neuroblastoma N2A cells. HMJ-53A also significantly left-shifted the steady-state inactivation curve by 12 mV. HMJ-53A, however, did not affect voltage-dependence of activation and the kinetics of channel activation. Intracellular application of this drug through patch pipette dialysis was ineffective at all in accelerating the slow current decay, suggesting that HMJ-53A acted extracellularly. Blockade of currents by HMJ-53A did not require an open state of channels. In addition, the inactivation time constants and percentage block of Kv currents in the presence of HMJ-53A were independent of the (i) degree of depolarization and (ii) intracellular K+ concentration. Therefore, this drug did not appear to directly occlude the outer channel pore during stimulation (depolarization). Taken together, our results suggest that HMJ-53A selectively affected (accelerated) the slow inactivation gating process of Kv channels, and could thus be a selective and novel probe for the inactivation gate.
显示于类别:	[Graduate Institute of Medical Science] Theses & dissertations

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