THE RELATIONSHIP OF BREVETOXIN LENGTH AND A-RING FUNCTIONALITY TO BINDING AND ACTIVITY IN NEURONAL SODIUM-CHANNELS
THE RELATIONSHIP OF BREVETOXIN LENGTH AND A-RING FUNCTIONALITY TO BINDING AND ACTIVITY IN NEURONAL SODIUM-CHANNELS
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DOI：
10.1016/1074-5521(95)90187-6
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发表时间：
1995-08-01
影响因子：
--
通讯作者：
BADEN, DG
中科院分区：
文献类型：
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作者：
GAWLEY, RE;REIN, KS;BADEN, DG
背景：Brevetoxins是聚醚梯形毒素，在纳摩尔浓度下具有鱼类毒性。它们与电压门控钠通道结合，引起四种不同的电生理效应：（i）激活电位的偏移;（ii）亚电导状态的发生;（iii）诱导通道的平均开放时间延长;和（iv）抑制通道失活。我们着手确定这些功能是否都需要相同的结构元素内的brevetoxin molecules.Results：几个合成制备的结构类似物的brevetoxin B突触体受体结合试验和功能性电生理测量进行了检查。截断的类似物在微摩尔浓度下不具有鱼毒性，显示出降低的受体结合亲和力，并且仅引起活化电位的转变而不影响平均开放时间或通道失活。类似物与A-环羰基去除结合到受体与纳摩尔亲和力，产生一个移动的激活电位和抑制失活，但不诱导更长的平均开放时间。A-环二醇减少的类似物显示低结合亲和力，但人口five subconductance states.Conclusions：我们的数据是一致的假设，即结合到钠通道需要一个细长的雪茄形分子，类似于30埃长。然而，短尾寒毒毒素的四种电生理学效应不是由单一结构特征产生的，因为它们可以通过使用修饰的配体来解耦，所述修饰的配体在此显示为部分钠通道激动剂。我们提出了一个详细的模型，解释了在短毒素类似物的影响的差异的结合的短毒素的通道。这些研究也提供了开发短毒素拮抗剂的潜力。
Background: Brevetoxins are polyether ladder toxins that are ichthyotoxic at nanomolar concentrations. They bind to voltage-gated sodium channels, causing four distinct electrophysiological effects: (i) a shift of activation potential; (ii) occurrence of subconductance states; (iii) induction of longer mean open times of the channel; and (iv) inhibition of channel inactivation. We set out to determine whether these functions all require the same structural elements within the brevetoxin molecules.Results: Several synthetically prepared structural analogs of brevetoxin B were examined in synaptosome receptor binding assays and by functional electrophysiological measurements. A truncated analog is not ichthyotoxic at micromolar concentrations, shows decreased receptor-binding affinity, and causes only a shift of activation potential without affecting mean open times or channel inactivation. An analog with the A-ring carbonyl removed binds to the receptor with nanomolar affinity, produces a shift of activation potential and inhibits inactivation, but does not induce longer mean open times. An analog in which the A-ring diol is reduced shows low binding affinity, yet populates five subconductance states.Conclusions: Our data are consistent with the hypothesis that binding to sodium channels requires an elongated cigar-shaped molecule, similar to 30 Angstrom long. The four electrophysiological effects of the brevetoxins are not produced by a single structural feature, however, since they can be decoupled by using modified ligands, which are shown here to be partial sodium channel agonists. We propose a detailed model for the binding of brevetoxins to the channel which explains the differences in the effects of the brevetoxin analogs. These studies also offer the potential for developing brevetoxin antagonists.