Local anesthetic inhibition of a bacterial sodium channel.
Local anesthetic inhibition of a bacterial sodium channel.
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DOI：
10.1085/jgp.201210779
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发表时间：
2012-06
期刊：
影响因子：
--
通讯作者：
Ahern CA
中科院分区：
文献类型：
--
作者：
Lee S;Goodchild SJ;Ahern CA
最近的结构突破与电压门控钠通道从Arcobacter butzleri表明，这样的细菌通道可能提供一个结构平台，以推进真核细胞钠通道门控和药理学的理解。因此，我们着手确定已知与真核NaVs相互作用的化合物是否也可以抑制来自耐盐芽孢杆菌和NaChBac的细菌通道，以及它们是否通过与其真核同源物类似的机制来抑制细菌通道。数据显示，原型局部麻醉剂（LA）利多卡因抑制静息NaChBac通道，解离常数（Kd）为260 µM，在药物存在下，通道显示左移稳态失活门控关系。细胞外应用QX-314表达的NaChBac通道对钠电流没有影响，而通过注射一团季铵衍生物的内部暴露迅速降低钠电导，与亲水性细胞质进入内部结合位点的途径一致。然而，外部应用的中性衍生物苯并咪唑抑制NaChBac通道，表明疏水途径也可以提供药物进入抑制通道。另外，雷诺嗪，一种假定的真核NaVs的预开放状态阻断剂，显示Kd为60 µM，并使NaChBac激活电压关系左移。在每种情况下，阻断增强进入通道的失活状态，这种效应可以通过简单的动力学方案很好地描述。这些数据表明，虽然存在显着差异，真核NaVs的LA块也发生在细菌钠通道和NaChBac共享药理学同源性的脊椎动物NaV同系物的静息状态。
Recent structural breakthroughs with the voltage-gated sodium channel from Arcobacter butzleri suggest that such bacterial channels may provide a structural platform to advance the understanding of eukaryotic sodium channel gating and pharmacology. We therefore set out to determine whether compounds known to interact with eukaryotic NaVs could also inhibit the bacterial channel from Bacillus halodurans and NaChBac and whether they did so through similar mechanisms as in their eukaryotic homologues. The data show that the archetypal local anesthetic (LA) lidocaine inhibits resting NaChBac channels with a dissociation constant (Kd) of 260 µM, and channels displayed a left-shifted steady-state inactivation gating relationship in the presence of the drug. Extracellular application of QX-314 to expressed NaChBac channels had no effect on sodium current, whereas internal exposure via injection of a bolus of the quaternary derivative rapidly reduced sodium conductance, consistent with a hydrophilic cytoplasmic access pathway to an internal binding site. However, the neutral derivative benzocaine applied externally inhibited NaChBac channels, suggesting that hydrophobic pathways can also provide drug access to inhibit channels. Alternatively, ranolazine, a putative preopen state blocker of eukaryotic NaVs, displayed a Kd of 60 µM and left-shifted the NaChBac activation-voltage relationship. In each case, block enhanced entry into the inactivated state of the channel, an effect that is well described by a simple kinetic scheme. The data suggest that although significant differences exist, LA block of eukaryotic NaVs also occurs in bacterial sodium channels and that NaChBac shares pharmacological homology to the resting state of vertebrate NaV homologues.
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影响因子：
2.4
作者：
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DOI：
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发表时间：
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