Bioelectricity Laboratory, Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, CA, USA.
Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, CA, USA.
Commun Biol. 2024 Aug 28;7(1):1059. doi: 10.1038/s42003-024-06752-y.
Pain and inflammation contribute immeasurably to reduced quality of life, yet modern analgesic and anti-inflammatory therapeutics can cause dependence and side effects. Here, we screened 1444 plant extracts, prepared primarily from native species in California and the United States Virgin Islands, against two voltage-gated K channels - T-cell expressed Kv1.3 and nociceptive-neuron expressed Kv7.2/7.3. A subset of extracts both inhibits Kv1.3 and activates Kv7.2/7.3 at hyperpolarized potentials, effects predicted to be anti-inflammatory and analgesic, respectively. Among the top dual hits are witch hazel and fireweed; polymodal modulation of multiple K channel types by hydrolysable tannins contributes to their dual anti-inflammatory, analgesic actions. In silico docking and mutagenesis data suggest pore-proximal extracellular linker sequence divergence underlies opposite effects of hydrolysable tannins on different Kv1 isoforms. The findings provide molecular insights into the enduring, widespread medicinal use of witch hazel and fireweed and demonstrate a screening strategy for discovering dual anti-inflammatory, analgesic small molecules.
疼痛和炎症极大地降低了生活质量，但现代的镇痛和抗炎治疗方法可能会导致依赖和副作用。在这里，我们筛选了 1444 种植物提取物，这些提取物主要来自加利福尼亚州和美属维尔京群岛的本地物种，针对两种电压门控 K 通道 - T 细胞表达的 Kv1.3 和伤害感受神经元表达的 Kv7.2/7.3。一部分提取物既能抑制 Kv1.3，又能在超极化电位下激活 Kv7.2/7.3，这两种作用分别预测具有抗炎和镇痛作用。排在前几位的双重命中物包括金缕梅和火草；可水解单宁对多种 K 通道类型的多模态调制有助于它们的双重抗炎和镇痛作用。计算机对接和突变数据表明，可水解单宁对不同 Kv1 亚型的相反作用的基础是孔近端细胞外连接序列的差异。这些发现为金缕梅和火草的持久广泛的药用提供了分子见解，并展示了一种发现双重抗炎、镇痛小分子的筛选策略。
