High-STX-affinity vs. low-STX-affinity Na+ channel subtypes in nerve, heart, and skeletal muscle.
High-STX-affinity vs. low-STX-affinity Na+ channel subtypes in nerve, heart, and skeletal muscle.
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神经、心脏和骨骼肌中高 STX 亲和力与低 STX 亲和力 Na 通道亚型。
DOI：
10.1111/j.1749-6632.1986.tb15585.x
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发表时间：
1986
影响因子：
5.2
通讯作者：
Rogart,RB
中科院分区：
文献类型：
--
作者：
Rogart,RB
河豚毒素（TTX）和蛤蚌毒素（STX）是两种小而强效的神经毒素，其作用依赖于在极低浓度下阻断Na+通道的高度特异性作用。大约在十年前，Ritchie， Strichartz和I ‘ ’介绍了一种新的方法，用‘ h， O交换标记高比活性的石蜡毒素（[’ HISTX]）。这提供了一种化学探针，已成功地用于表征大量神经和骨骼肌制剂中具有STX“高亲和力”受体的Na+通道。第二种Na+通道具有“低亲和力”的STX和TTX受体，已经被假设为解释在许多制剂中发现的“TTX不敏感”动作电位（AP）。尽管HISTX具有高比活性，但具有低亲和力STX受体的Na通道在许多研究中都没有被检测到，而其他测量表明这些通道似乎存在。在高亲和STX受体的制剂中，快速通透性的生理阻滞增加到Na+，这是在纳摩尔浓度范围内动作电位上升的基础。这与3h标记的STX和TTX与Na+通道结合的平衡解离常数（Kd值）密切相关。这种生理效应与药理学结合特性之间的密切联系使得它们可以作为研究Na+通道蛋白的药理学标记物。HJSTX和HITTX已成功用于估计可兴奋膜中的Na+通道密度和分布。探索通道毒素结合部位的化学性质，并从鳗鱼电斑、大鼠骨骼肌和大鼠大脑中纯化Na+通道。在维持Na+依赖性毒素不敏感AP的组织中，STX和TTX对AP的阻断发生在毒素浓度比具有“毒素敏感”AP的可兴奋膜高2-4个数量级的情况下，后者被纳摩尔浓度的STX和TTX阻断。Redfern和Thesleff首先在“失神经哺乳动物骨骼肌”中描述了这些ttx不敏感的APs，随后在其他哺乳动物组织中广泛分布，包括新生哺乳动物骨骼肌、哺乳动物心肌、小鼠体内和培养的背根神经节细胞、培养的哺乳动物骨骼肌和L6细胞。
Tetrodotoxin (TTX) and saxitoxin (STX), two small and highly potent neurotoxins, depend for their effect on a highly specific action of blocking Na+ channels at extremely low concentrations. About ten years ago, Ritchie, Strichartz, and I’introduced a novel way of exchange-labeling saxitoxin ([’HISTX) with’H, O to high specific activity. This has provided a chemical probe that has been used with great success to characterize Na+ channels with “high-affinity” receptors for STX in a large number of nerve and skeletal muscle preparations?*’A second type of Na+ channel with a “low-affinity” STX and TTX receptor has been hypothesized to account for a “TTX-insensitive” action potential (AP) found in a number of preparations. Despite the high specific activity of [’HISTX, Na’channels with low-affinity STX receptors have eluded detection in many studies” 2 of preparations where other measurements suggest that these channels seem to be present. In preparations with high-affinity STX receptors, physiological block of the rapid permeability increase to Na+ which underlies the rising phase of the action potential occurs in the nanomolar concentration range. This correlates well with the equilibrium dissociation constant (Kd value) for binding of 3H-labeled STX and TTX to the Na+ channel. This close correlation between physiological effects and pharmacological binding properties has allowed their use as pharmacologic markers to study the Na+ channel protein.[’HJSTX and [’HITTX have been used successfully to estimate Na+ channel density and distribution in excitable membranes,’.’to probe the chemical nature of the channel’s toxin binding site,’and to allow purification of the Na+ channel from eel electroplaque, rat skeletal muscle, and rat brain. I4J6 In tissues’ found to maintain Na+-dependent toxin-insensitive APs, block of the AP by STX and TTX occurs at concentrations of toxin that are 2-4 orders of magnitude greater than in excitable membranes with “toxin-sensitive” APs, which are blocked by nanomolar concentrations of STX and TTX. These TTX-insensitive APs, first described by Redfern and Thesleff’’in denervated mammalian skeletal muscle, have subsequently been found in widespread distribution in other mammalian tissues,’including newborn mammalian skeletal muscle, mammalian cardiac muscle, mouse dorsal root ganglion cells in vivo and in culture, cultured mammalian skeletal muscle, and L6 cells.