Department of Chemistry, Stanford University, 337 Campus Drive, Stanford, CA 94305, USA.
Cardiovascular Research Institute, University of California, San Francisco, Box 3122, 555 Mission Bay Boulevard South, Rm. 452Z, San Francisco, CA 94158-9001, USA.
Cell Chem Biol. 2022 Apr 21;29(4):615-624.e5. doi: 10.1016/j.chembiol.2021.12.003. Epub 2021 Dec 27.
Voltage-gated sodium channels (Nas) 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 Na subtypes (rNa1.4 and hNa1.5). Two of these compounds, BTX-B and BTX-Hx, 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 Na modulators as a unique reagent that separates inactivation processes. These findings are supported by functional studies with bacterial Nas (BacNas) that lack a fast inactivation gate. The availability of BTX-yne should advance future efforts aimed at understanding Na gating mechanisms and designing allosteric regulators of Na activity.
电压门控钠离子通道（Nas）是许多急性毒物的靶标。这些药物中的许多都是通道活性的变构调节剂，是研究通道功能的有力化学工具。在此，我们详细介绍了使用河豚毒素（BTX）的研究，BTX 是一种有效的甾体胺，以及通过从头合成针对重组 Na 亚型（rNa1.4 和 hNa1.5）制备的三种酯衍生物。这两种化合物，BTX-B 和 BTX-Hx，与 BTX 功能等效，使通道激活超极化并阻断快速和慢速失活。BTX-yne-a C20-庚炔酸酯是一个明显的例外，它消除了快速失活但不影响慢速失活。BTX-yne 在其他 Na 调节剂中作为一种独特的试剂，可区分失活过程，这种特性将其区分开来。这些发现得到了缺乏快速失活门的细菌 Nas（BacNas）功能研究的支持。BTX-yne 的可用性应有助于未来努力，旨在了解 Na 门控机制和设计 Na 活性的变构调节剂。
