An anionic ryanoid, 10-O-succinoylryanodol, provides insights into the mechanisms governing the interaction of ryanoids and the subsequent altered function of ryanodine-receptor channels.
An anionic ryanoid, 10-O-succinoylryanodol, provides insights into the mechanisms governing the interaction of ryanoids and the subsequent altered function of ryanodine-receptor channels.
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阴离子 ryanoids 10-O-succinoylryanodol 可深入了解 ryanoids 相互作用的机制以及随后改变的 ryanodine 受体通道功能。
DOI：
10.1085/jgp.200208753
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发表时间：
2003
期刊：
影响因子：
--
通讯作者：
Williams,AlanJ
中科院分区：
文献类型：
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作者：
Tanna,Bhavna;Welch,William;Ruest,Luc;Sutko,JohnL;Williams,AlanJ
1心脏医学，国家心肺研究所，帝国理工学院，伦敦SW 3 6LY，英国2生物化学系和3药理学系，内华达州医学院，里诺，NV 89557 4化学系，舍布鲁克大学，舍布鲁克，魁北克JK 1 2 R1，加拿大摘要我们研究了一种新的阴离子ryanoid，10-O-琥珀酰ryanodol，与电压钳条件下的单个哺乳动物心肌ryanodine受体通道。与迄今为止检查的所有ryanoids的情况一样，10-O-succinoylryanodol与单个RyR通道的相互作用在通道门控和离子易位速率方面产生了深刻的改变。在持续存在的ryanoid的通道波动之间的正常和修改的门控期间，表明可逆的相互作用的配体与其受体。与大多数ryanoids，我们观察到一系列不同的分数电导状态的RyR在10-O-succinoylryanodol的存在下。我们表明，10-O-succinoylryanodol是一个非常灵活的分子，并提出每个分数电导状态产生的RyR通道的ryanoid分子的不同构象的相互作用。10-O-琥珀酰ryanodol修饰通道的可能性取决于跨膜保持电位。这种新型的阴离子ryanoid与以前的数据与阳离子和中性ryanoid通道修饰的电压依赖性的比较表明，跨膜电位的RyR通道修饰的概率ryanoid的结果从受体亲和力的改变的主要影响。这些调查还表明，电荷的ryanoid有一个主要的影响的配体与其受体的关联率，表明离子相互作用可能参与这个反应。
1Cardiac Medicine, National Heart and Lung Institute, Imperial College of Science, Technology, and Medicine, London SW3 6LY, UK 2Department of Biochemistry, and 3Department of Pharmacology, University of Nevada School of Medicine, Reno, NV 89557 4Department of Chemistry, University of Sherbrooke, Sherbrooke, Quebec JK1 2R1, Canada abstract We have investigated the interactions of a novel anionic ryanoid, 10-O-succinoylryanodol, with individual mammalian cardiac muscle ryanodine receptor channels under voltage clamp conditions. As is the case for all ryanoids so far examined, the interaction of 10-O-succinoylryanodol with an individual RyR channel produces profound alterations in both channel gating and rates of ion translocation. In the continued presence of the ryanoid the channel fluctuates between periods of normal and modified gating, indicating a reversible interaction of the ligand with its receptor. Unlike the majority of ryanoids, we observe a range of different fractional conductance states of RyR in the presence of 10-O-succinoylryanodol. We demonstrate that 10-O-succinoylryanodol is a very flexible molecule and propose that each fractional conductance state arises from the interaction of a different conformer of the ryanoid molecule with the RyR channel. The probability of channel modification by 10-O-succinoylryanodol is dependent on the transmembrane holding potential. Comparison of the voltage dependence of channel modification by this novel anionic ryanoid with previous data obtained with cationic and neutral ryanoids reveals that the major influence of transmembrane potential on the probability of RyR channel modification by ryanoids results from an alteration in receptor affinity. These investigations also demonstrate that the charge of the ryanoid has a major influence on the rate of association of the ligand with its receptor indicating that ionic interactions are likely to be involved in this reaction.