Mitragynine and its potential blocking effects on specific cardiac potassium channels.
Mitragyna speciosa Korth is known for its euphoric properties and is frequently used for recreational purposes. Several poisoning and fatal cases involving mitragynine have been reported but the underlying causes remain unclear. Human ether-a-go-go-related gene (hERG) encodes the cardiac IKr current which is a determinant of the duration of ventricular action potentials and QT interval. On the other hand, IK1, a Kir current mediated by Kir2.1 channel and IKACh, a receptor-activated Kir current mediated by GIRK channel are also known to be important in maintaining the cardiac function. This study investigated the effects of mitragynine on the current, mRNA and protein expression of hERG channel in hERG-transfected HEK293 cells and Xenopus oocytes. The effects on Kir2.1 and GIRK channels currents were also determined in the oocytes. The hERG tail currents following depolarization pulses were inhibited by mitragynine with an IC50 value of 1.62μM and 1.15μM in the transfected cell line and Xenopus oocytes, respectively. The S6 point mutations of Y652A and F656A attenuated the inhibitor effects of mitragynine, indicating that mitragynine interacts with these high affinity drug-binding sites in the hERG channel pore cavity which was consistent with the molecular docking simulation. Interestingly, mitragynine does not affect the hERG expression at the transcriptional level but inhibits the protein expression. Mitragynine is also found to inhibit IKACh current with an IC50 value of 3.32μM but has no significant effects on IK1. Blocking of both hERG and GIRK channels may cause additive cardiotoxicity risks.
Malaysian Institute of Pharmaceuticals & Nutraceuticals, NIBM, Ministry of Science, Technology & Innovation (MOSTI), Pulau Pinang, Malaysia.
Yea Lu
YL
Tay
Malaysian Institute of Pharmaceuticals & Nutraceuticals, NIBM, Ministry of Science, Technology & Innovation (MOSTI), Pulau Pinang, Malaysia.
Yi Fan
YF
Teah
Malaysian Institute of Pharmaceuticals & Nutraceuticals, NIBM, Ministry of Science, Technology & Innovation (MOSTI), Pulau Pinang, Malaysia.
Yoong Min
YM
Chong
Clinical Research Center, Hospital Seberang Jaya, Kementerian Kesihatan Malaysia, Pulau Pinang, Malaysia.
Mohd Fadzly Amar
MFA
Jamil
Institute of Physiology, University of Wurzburg, Wurzburg, Germany.
Sina
S
Kollert
Atta-ur-Rahman Institute for Natural Product Discovery, Universiti Teknologi MARA (UiTM), Selangor Darul Ehsan, Malaysia.
Mohd Ilham
MI
Adenan
Pharmaceutical Design & Simulation (PhDS) Laboratory, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Pulau Pinang, Malaysia.
Habibah Abdul
HA
Wahab
Institute of Physiology, University of Wurzburg, Wurzburg, Germany.
Frank
F
Döring
Institute of Physiology, University of Wurzburg, Wurzburg, Germany.
Erhard
E
Wischmeyer
Malaysian Institute of Pharmaceuticals & Nutraceuticals, NIBM, Ministry of Science, Technology & Innovation (MOSTI), Pulau Pinang, Malaysia; Advanced Medical and Dental Institute, Universiti Sains Malaysia, Pulau Pinang, Malaysia. Electronic address: tanml@usm.my.
Mei Lan
ML
Tan
D000818:Animals; D000077743:Diterpene Alkaloids; D000072237:ERG1 Potassium Channel / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D057809:HEK293 Cells; D006321:Heart / Q000502:physiology; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D009865:Oocytes / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D046948:Secologanin Tryptamine Alkaloids / Q000494:pharmacology*; D014981:Xenopus
D000077743:Diterpene Alkaloids; D000072237:ERG1 Potassium Channel; C000606913:KCNH2 protein, human; D026902:Potassium Channel Blockers; D012333:RNA, Messenger; D046948:Secologanin Tryptamine Alkaloids; C001801:mitragynine
Cardiotoxicity; GIRK; Kir2.1; Mitragynine; hERG