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Differential effects of modified batrachotoxins on voltage-gated sodium channel fast and slow inactivation
Cell Chemical Biology ( IF 8.6 ) Pub Date : 2021-12-27 , DOI: 10.1016/j.chembiol.2021.12.003
Tim M G MacKenzie 1 , Fayal Abderemane-Ali 2 , Catherine E Garrison 1 , Daniel L Minor 3 , J Du Bois 1
Affiliation  

Voltage-gated sodium channels (NaVs) are targets for a number of acute poisons. Many of these agents act as allosteric modulators of channel activity and serve as powerful chemical tools for understanding channel function. Herein, we detail studies with batrachotoxin (BTX), a potent steroidal amine, and three ester derivatives prepared through de novo synthesis against recombinant NaV subtypes (rNaV1.4 and hNaV1.5). Two of these compounds, BTX-B and BTX-cHx, are functionally equivalent to BTX, hyperpolarizing channel activation and blocking both fast and slow inactivation. BTX-yne—a C20-n-heptynoate ester—is a conspicuous outlier, eliminating fast but not slow inactivation. This property differentiates BTX-yne among other NaV modulators as a unique reagent that separates inactivation processes. These findings are supported by functional studies with bacterial NaVs (BacNaVs) that lack a fast inactivation gate. The availability of BTX-yne should advance future efforts aimed at understanding NaV gating mechanisms and designing allosteric regulators of NaV activity.



中文翻译:

修饰的蝙蝠毒素对电压门控钠通道快速和缓慢失活的不同影响

电压门控钠通道 (Na V s) 是许多急性毒物的目标。这些试剂中有许多充当通道活动的变构调节剂,并作为了解通道功能的强大化学工具。在此,我们详细研究了蝙蝠毒素 (BTX)、一种有效的甾体胺和通过从头合成制备的三种针对重组 Na V亚型(rNa V 1.4 和 hNa V 1.5)的酯衍生物。这些化合物中的两种,BTX-B 和 BTX- c Hx,在功能上等同于 BTX,超极化通道激活并阻断快速和慢速失活。BTX-yne——一种 C20- n-庚酸酯 - 是一个明显的异常值,可快速但不慢地消除失活。这一特性使 BTX-yne 与其他 Na V调节剂区别开来,作为一种独特的试剂,可以分离失活过程。这些发现得到了对缺乏快速灭活门的细菌 Na V s (BacNa V s) 的功能研究的支持。BTX-yne 的可用性应推动未来旨在理解 Na V门控机制和设计 Na V活动的变构调节器的努力。

更新日期:2021-12-27
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