Mitragynine，一种欣快的化合物，可抑制hERG1a / 1b通道电流，并上调HEK293-hERG1a / 1b细胞中hERG1a-Hsp90的复合。,Scientific Reports

当前位置： X-MOL 学术 › Sci. Rep. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Mitragynine，一种欣快的化合物，可抑制hERG1a / 1b通道电流，并上调HEK293-hERG1a / 1b细胞中hERG1a-Hsp90的复合。
Scientific Reports ( IF 3.8 ) Pub Date : 2019-12-24 , DOI: 10.1038/s41598-019-56106-6
Yea Lu Tay ₁ , Azimah Amanah ₁ , Mohd Ilham Adenan ₂ , Habibah Abdul Wahab ₃ , Mei Lan Tan _{1,

3,

4}

Affiliation

Mitragyna speciosa Korth（M. speciosa）已被广泛用作娱乐产品，但是，人们对该植物的滥用潜力和毒性越来越关注。据报道，有几个涉及克拉托姆和米塔吉宁的中毒和致命病例，但其根本原因仍不清楚。人类以太相关基因1（hERG1）编码心脏快速延迟整流钾电流（IKr）下的成孔亚基。IKr的药理学阻断可导致获得性长QT综合征，从而导致致命的心律失常。这项研究的目的是阐明mitragynine诱导的抑制hERG1a / 1b电流的机制。电生理实验是使用Port-a-Patch系统进行的。定量RT-PCR，蛋白质印迹分析，免疫荧光法和免疫共沉淀法用于测定米他宁碱对hERG1a / 1b表达和hERG1胞浆伴侣相互作用的影响。发现Mitragynine可抑制IKr电流，IC50值为332.70 nM。它会导致完全糖基化（fg）的hERG1a蛋白表达显着降低，但会同时上调核心糖基化（cg）的表达和hERG1a-Hsp90复合物，提示可能受损的hERG1a转运。总之，米塔吉宁通过较低浓度的直接通道阻断作用抑制hERG1a / 1b电流，但是在较高浓度下，它会上调hERG1a-Hsp90的复合物，这可能对通道运输具有抑制作用。发现Mitragynine可抑制IKr电流，IC50值为332.70 nM。它会导致全糖基化（fg）的hERG1a蛋白表达显着降低，但会同时上调核心糖基化（cg）的表达和hERG1a-Hsp90复合物，提示可能受损的hERG1a转运。总之，米塔吉宁通过较低浓度的直接通道阻断作用抑制hERG1a / 1b电流，但是在较高浓度下，它会上调hERG1a-Hsp90的复合物，这可能对通道运输具有抑制作用。发现Mitragynine可抑制IKr电流，IC50值为332.70 nM。它会导致完全糖基化（fg）的hERG1a蛋白表达显着降低，但会同时上调核心糖基化（cg）的表达和hERG1a-Hsp90复合物，提示可能受损的hERG1a转运。总之，米塔吉宁通过较低浓度的直接通道阻断作用抑制hERG1a / 1b电流，但是在较高浓度下，它会上调hERG1a-Hsp90的复合物，这可能对通道运输具有抑制作用。

"点击查看英文标题和摘要"

Mitragynine, an euphoric compound inhibits hERG1a/1b channel current and upregulates the complexation of hERG1a-Hsp90 in HEK293-hERG1a/1b cells.

Mitragyna speciosa Korth (M. speciosa) has been widely used as a recreational product, however, there are growing concerns on the abuse potentials and toxicity of the plant. Several poisoning and fatal cases involving kratom and mitragynine have been reported but the underlying causes remain unclear. The human ether-a-go-go-related gene 1 (hERG1) encodes the pore-forming subunit underlying cardiac rapidly delayed rectifier potassium current (IKr). Pharmacological blockade of the IKr can cause acquired long QT syndrome, leading to lethal cardiac arrhythmias. This study aims to elucidate the mechanisms of mitragynine-induced inhibition on hERG1a/1b current. Electrophysiology experiments were carried out using Port-a-Patch system. Quantitative RT-PCR, Western blot analysis, immunofluorescence and co-immunoprecipitation methods were used to determine the effects of mitragynine on hERG1a/1b expression and hERG1-cytosolic chaperones interaction. Mitragynine was found to inhibit the IKr current with an IC50 value of 332.70 nM. It causes a significant reduction of the fully-glycosylated (fg) hERG1a protein expression but upregulates both core-glycosylated (cg) expression and hERG1a-Hsp90 complexes, suggesting possible impaired hERG1a trafficking. In conclusion, mitragynine inhibits hERG1a/1b current through direct channel blockade at lower concentration, but at higher concentration, it upregulates the complexation of hERG1a-Hsp90 which may be inhibitory towards channel trafficking.

更新日期：2019-12-25

点击分享查看原文

点击收藏

公开下载

阅读更多本刊新发论文本刊介绍/投稿指南