Ryanoid modification of the cardiac muscle ryanodine receptor channel results in relocation of the tetraethylammonium binding site.
Ryanoid modification of the cardiac muscle ryanodine receptor channel results in relocation of the tetraethylammonium binding site.
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Ryanoid 对心肌兰尼碱受体通道的修饰导致四乙铵结合位点的重新定位。
DOI：
10.1085/jgp.117.5.385
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发表时间：
2001
期刊：
影响因子：
--
通讯作者：
Williams,AJ
中科院分区：
文献类型：
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作者：
Tanna,B;Welch,W;Ruest,L;Sutko,JL;Williams,AJ
来自 * 英国帝国理工学院国家心肺研究所心脏医学系，伦敦SW 3 6LY;内华达州大学医学院生物化学系和药理学系，里诺，内华达州89557;和化学系，舍布鲁克大学，舍布鲁克，魁北克J1 K 2 R1，兰尼碱及其衍生物与兰尼碱受体（RyR）通道上的高亲和力结合位点的相互作用导致通道功能的特征性改变。在所有情况下，通道开放概率显著增加，单通道电流幅度减小。的ryanoid修改的电导状态的幅度是由配体的结构特征。在ryanodine修饰的电导状态下的离子处理的研究已经确定，降低的电导是由于通道对渗透离子的亲和力和通道内离子的相对渗透性两者的变化引起的（林赛，ARG，A.廷克和AJ威廉姆斯。1994. 104：425-447）。有人提出，这些改变是由于结合的ryanoid诱导的通道结构的重组。本文报道的实验为类ryanoid诱导的RyR重组提供了直接证据。TEA是RyR的浓度和电压依赖性阻断剂，在不存在ryanoids的情况下。我们研究了TEA在21-amino-9-hydroxyryanodine、21-azido-9-hydroxyryanodine、ryanodol和21-p-nitrobenzoamino-9-hydroxyryanodine诱导的RyR未修饰开放态和修饰电导态下对K电流的阻断作用。块的电压依赖性的分析表明，ryanoids与RyR的相互作用导致在此参数的改变与跨越通道的电压降内的TEA阻断位点的明显的重新定位和通道的亲和力的改变为阻滞剂。这些参数的变化程度广泛相关的渗透阳离子诱导的ryanoids的电导的变化，这表明RyR通道结构的ryanoids的修改可能是这两种现象的基础。
From the* Department of Cardiac Medicine, National Heart and Lung Institute, Imperial College of Science, Technology and Medicine, London SW3 6LY, United Kingdom;‡ Department of Biochemistry and § Department of Pharmacology, University of Nevada School of Medicine, Reno, Nevada 89557; and Department of Chemistry, University of Sherbrooke, Sherbrooke, Quebec J1K 2R1, Canada abstract The interaction of ryanodine and derivatives of ryanodine with the high affinity binding site on the ryanodine receptor (RyR) channel brings about a characteristic modification of channel function. In all cases, channel open probability increases dramatically and single-channel current amplitude is reduced. The amplitude of the ryanoid-modified conductance state is determined by structural features of the ligand. An investigation of ion handling in the ryanodine-modified conductance state has established that reduced conductance results from changes in both the affinity of the channel for permeant ions and the relative permeability of ions within the channel (Lindsay, ARG, A. Tinker, and AJ Williams. 1994. J. Gen. Physiol. 104: 425–447). It has been proposed that these alterations result from a reorganization of channel structure induced by the binding of the ryanoid. The experiments reported here provide direct evidence for ryanoid-induced restructuring of RyR. TEA is a concentration-and voltage-dependent blocker of RyR in the absence of ryanoids. We have investigated block of K current by TEA in the unmodified open state and modified conductance states of RyR induced by 21-amino-9-hydroxyryanodine, 21-azido-9-hydroxyryanodine, ryanodol, and 21-p-nitrobenzoylamino-9-hydroxyryanodine. Analysis of the voltage dependence of block indicates that the interaction of ryanoids with RyR leads to an alteration in this parameter with an apparent relocation of the TEA blocking site within the voltage drop across the channel and an alteration in the affinity of the channel for the blocker. The degree of change of these parameters correlates broadly with the change in conductance of permeant cations induced by the ryanoids, indicating that modification of RyR channel structure by ryanoids is likely to underlie both phenomena.