Abstract
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.
Highlights
Mitragyna speciosa Korth (M. speciosa) has been widely used as a recreational product, there are growing concerns on the abuse potentials and toxicity of the plant
HERG1a protein was identified by bands at 155 kDa [fully-glycosylated, mature form] and 135 kDa [core-glycosylated precursor form], whereas hERG1b protein was identified by bands at 95 kDa and 80 kDa, respectively (Supplementary Figs. 1–6)
With repolarization to more negative voltages, hERG1a/1b current recovered from inactivation and subsequently underwent voltage-dependent decay
Summary
Mitragyna speciosa Korth (M. speciosa) has been widely used as a recreational product, 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. 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 hERG1aHsp[90] complexes, suggesting possible impaired hERG1a trafficking. Kratom leaves have been used by natives to treat common illnesses and are popular for their energizing and pain alleviating effects This plant is known to possess psychostimulant- and opiate-like properties, depending on the dosage taken[1,3,5]. All measurements were carried out at room temperature In another fatal kratom toxicity involving a young male, therapeutic levels of over-the-counter cold medications, benzodiazepines and mitragynine was detected simultaneously. Kratom has been reported to cause serious adverse effects, such as elevated blood pressure, nephrotoxic effects, impaired cognition and behavior and hepatic failure[2,7,14,15,16]
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