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

• Published in: Scientific reports 2019-12, Vol.9 (1), p.19757-16, Article 19757
• Main Authors: Tay, Yea Lu, Amanah, Azimah, Adenan, Mohd Ilham, Wahab, Habibah Abdul, Tan, Mei Lan
• Format: Article
• Language: English
• Subjects: 14/19; 38/77; 631/154/570; 64; 692/4019/592; 82; 82/80; 9/74; Abuse; Chaperones; Drug withdrawal; Electrophysiology; Ether-A-Go-Go Potassium Channels - metabolism; Experiments; Heart; HEK293 Cells; HSP90 Heat-Shock Proteins - metabolism; Hsp90 protein; Humanities and Social Sciences; Humans; Immunofluorescence; Immunoprecipitation; Long QT syndrome; Membrane Potentials - drug effects; multidisciplinary; Multiprotein Complexes - metabolism; Narcotics; Polymerase chain reaction; Potassium; Protein expression; Protein transport; Proteins; Science; Science (multidisciplinary); Secologanin Tryptamine Alkaloids - pharmacology; Toxicity; Up-Regulation - drug effects
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-56106-6

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 ( I Kr ). Pharmacological blockade of the I Kr 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 I Kr current with an IC 50 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.