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The Tunicate Metabolite 2-(3,5-Diiodo-4-methoxyphenyl)ethan-1-amine Targets Ion Channels of Vertebrate Sensory Neurons
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2021-08-23 , DOI: 10.1021/acschembio.1c00328 Noemi D Paguigan 1 , Yannan Yan 2 , Manju Karthikeyan 3 , Kevin Chase 3 , Jackson Carter 3 , Lee S Leavitt 3 , Albebson L Lim 1 , Zhenjian Lin 1 , Tosifa Memon 4 , Sean Christensen 3 , Bo H Bentzen 2 , Nicole Schmitt 2 , Christopher A Reilly 4 , Russell W Teichert 3 , Shrinivasan Raghuraman 3 , Baldomero M Olivera 3 , Eric W Schmidt 1
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2021-08-23 , DOI: 10.1021/acschembio.1c00328 Noemi D Paguigan 1 , Yannan Yan 2 , Manju Karthikeyan 3 , Kevin Chase 3 , Jackson Carter 3 , Lee S Leavitt 3 , Albebson L Lim 1 , Zhenjian Lin 1 , Tosifa Memon 4 , Sean Christensen 3 , Bo H Bentzen 2 , Nicole Schmitt 2 , Christopher A Reilly 4 , Russell W Teichert 3 , Shrinivasan Raghuraman 3 , Baldomero M Olivera 3 , Eric W Schmidt 1
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Marine tunicates produce defensive amino-acid-derived metabolites, including 2-(3,5-diiodo-4-methoxyphenyl)ethan-1-amine (DIMTA), but their mechanisms of action are rarely known. Using an assay-guided approach, we found that out of the many different sensory cells in the mouse dorsal root ganglion (DRG), DIMTA selectively affected low-threshold cold thermosensors. Whole-cell electrophysiology experiments using DRG cells, channels expressed in Xenopus oocytes, and human cell lines revealed that DIMTA blocks several potassium channels, reducing the magnitude of the afterhyperpolarization and increasing the baseline intracellular calcium concentration [Ca2+]i of low-threshold cold thermosensors. When injected into mice, DIMTA increased the threshold of cold sensation by >3 °C. DIMTA may thus serve as a lead in the further design of compounds that inhibit problems in the cold-sensory system, such as cold allodynia and other neuropathic pain conditions.
中文翻译：
被囊类代谢物 2-(3,5-Diiodo-4-methoxyphenyl)ethan-1-amine 靶向脊椎动物感觉神经元的离子通道
海洋被囊类动物产生防御性氨基酸衍生代谢物，包括 2-(3,5-diiodo-4-methoxyphenyl)ethan-1-amine (DIMTA)，但它们的作用机制鲜为人知。使用测定指导的方法，我们发现在小鼠背根神经节 (DRG) 中的许多不同感觉细胞中，DIMTA 选择性地影响低阈值冷热传感器。使用 DRG 细胞、非洲爪蟾卵母细胞中表达的通道和人类细胞系的全细胞电生理学实验表明，DIMTA 阻断了几个钾通道，降低了后超极化的幅度并增加了基线细胞内钙浓度 [Ca 2+ ] i低阈值冷热传感器。当注射到小鼠体内时，DIMTA 将冷感阈值提高了 >3°C。因此，DIMTA 可以作为进一步设计化合物的先导，以抑制冷感觉系统中的问题，例如冷异常性疼痛和其他神经性疼痛病症。
更新日期：2021-09-17
中文翻译：
被囊类代谢物 2-(3,5-Diiodo-4-methoxyphenyl)ethan-1-amine 靶向脊椎动物感觉神经元的离子通道
海洋被囊类动物产生防御性氨基酸衍生代谢物，包括 2-(3,5-diiodo-4-methoxyphenyl)ethan-1-amine (DIMTA)，但它们的作用机制鲜为人知。使用测定指导的方法，我们发现在小鼠背根神经节 (DRG) 中的许多不同感觉细胞中，DIMTA 选择性地影响低阈值冷热传感器。使用 DRG 细胞、非洲爪蟾卵母细胞中表达的通道和人类细胞系的全细胞电生理学实验表明，DIMTA 阻断了几个钾通道，降低了后超极化的幅度并增加了基线细胞内钙浓度 [Ca 2+ ] i低阈值冷热传感器。当注射到小鼠体内时，DIMTA 将冷感阈值提高了 >3°C。因此，DIMTA 可以作为进一步设计化合物的先导，以抑制冷感觉系统中的问题，例如冷异常性疼痛和其他神经性疼痛病症。
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