Bosmans Frank, Martin-Eauclaire Marie-France, Swartz Kenton J
Molecular Physiology and Biophysics Section, Porter Neuroscience Research Center, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA.
Nature. 2008 Nov 13;456(7219):202-8. doi: 10.1038/nature07473.
Voltage-activated sodium (Na(v)) channels are crucial for the generation and propagation of nerve impulses, and as such are widely targeted by toxins and drugs. The four voltage sensors in Na(v) channels have distinct amino acid sequences, raising fundamental questions about their relative contributions to the function and pharmacology of the channel. Here we use four-fold symmetric voltage-activated potassium (K(v)) channels as reporters to examine the contributions of individual S3b-S4 paddle motifs within Na(v) channel voltage sensors to the kinetics of voltage sensor activation and to forming toxin receptors. Our results uncover binding sites for toxins from tarantula and scorpion venom on each of the four paddle motifs in Na(v) channels, and reveal how paddle-specific interactions can be used to reshape Na(v) channel activity. One paddle motif is unique in that it slows voltage sensor activation, and toxins selectively targeting this motif impede Na(v) channel inactivation. This reporter approach and the principles that emerge will be useful in developing new drugs for treating pain and Na(v) channelopathies.
电压门控性钠（Na(v)）通道对于神经冲动的产生和传导至关重要，因此广泛成为毒素和药物的作用靶点。Na(v)通道中的四个电压传感器具有不同的氨基酸序列，这引发了关于它们对通道功能和药理学相对贡献的基本问题。在这里，我们使用四重对称电压门控性钾（K(v)）通道作为报告分子，来研究Na(v)通道电压传感器内各个S3b-S4桨状基序对电压传感器激活动力学以及形成毒素受体的贡献。我们的结果揭示了狼蛛和蝎毒毒素在Na(v)通道的四个桨状基序上的结合位点，并揭示了桨状基序特异性相互作用如何用于重塑Na(v)通道活性。一个桨状基序的独特之处在于它会减缓电压传感器的激活，而选择性靶向该基序的毒素会阻碍Na(v)通道失活。这种报告分子方法以及由此产生的原理将有助于开发治疗疼痛和Na(v)通道病的新药。
