Molecular Mechanisms Of Mitragynine Inhibition On Herg1a/1b Channel
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Date
2018-04
Authors
Tay, Yea Lu
Journal Title
Journal ISSN
Volume Title
Publisher
Universiti Sains Malaysia
Abstract
The leaves of Mitragyna speciosa Korth (M. speciosa), commonly known as ketum in Malaysia, have been widely used to treat common illnesses such as intestinal infections, muscle pain, cough, diarrhea, diabetes, hypertension and to improve blood circulation. Nevertheless, there are growing concerns about the safety and abuse or misuse potentials of the plant which exhibits addictive effects. The safety profile of the plant is not fully elucidated. 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, which may lead to lethal cardiac arrhythmias. Hence, this study aims to investigate the effects of mitragynine, the major bioactive compound derived from the leave extracts of ketum, on hERG1a/1b channel inhibition, using both in silico and in vitro approaches. Docking simulations were performed using a hERG1 homology model and their molecular interactions and binding affinities were analyzed. A recombinant HEK293-hERG1a/1b cell line was established and subsequently used to evaluate the effects of mitragynine on hERG1a/1b current and mRNA expression using whole cell patch clamp and RT-qPCR analyses respectively. In addition, the protein expression of hERG1a/1b channels was studied using both Western blot and immunofluorescence analyses. In silico study shows that mitragynine is likely a hERG1 inhibitor by forming π interactions with the important residues, Tyr652 and Phe656, of the hERG1 channel. Whole cell patch clamp system using the recombinant HEK293-hERG1a/1b cell line was successfully established and verified using several known hERG1 blockers.
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Keywords
Molecular mechanisms of mitragynine , inhibition on herg1a/1b channel