Blockade of the Human Ether A-Go-Go-Related Gene (hERG) Potassium Channel by Fentanyl
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Fentanyl poses a serious health concern, with abuse and death rates rising over recent years. Despite the high number of overdose deaths attributed to fentanyl, the complete molecular mechanisms of such deaths have not been well-defined. Although activation of opioid receptors in the brainstem causes respiratory depression, in most cases of drug-induced sudden death cardiac arrhythmias are implicated. Therefore, we posited that disruption of cardiac electrophysiology may contribute to fentanyl-induced death. The human ether-a-go-go-related gene (hERG) encodes the pore-forming subunit of the rapidly activating delayed rectifier potassium channel (IKr). Drug-mediated disruption of hERG function is the primary cause of acquired long QT syndrome, which predisposes affected individuals to ventricular arrhythmias and sudden death. Therefore, we investigated the effects of fentanyl on hERG channels. The effects of norfentanyl, the main metabolite, and naloxone, an antidote used in fentanyl overdose, were also examined. Currents of hERG channels stably expressed in HEK293 cells were recorded using whole-cell voltage-clamp. When hERG tail currents upon −50 mV repolarization after a 50 mV depolarization were analyzed, fentanyl and naloxone blocked hERG current (IhERG) with IC50 values of 0.9 and 74.3 μM, respectively, whereas norfentanyl did not block. The reduction of IhERG by fentanyl was not antagonized by naloxone, indicating that the reduction was not through activation of opioid receptors. An interesting finding is that fentanyl-mediated block of IhERG was voltage-dependent. Consequently, when a human ventricular action potential waveform voltage protocol was used, fentanyl blocked IhERG with an IC50 of 0.3 μM, which is within the range of blood concentrations after overdose deaths in humans. Furthermore, fentanyl (0.5 μM) blocked IKr and prolonged action potential duration in ventricular myocytes isolated from neonatal rats. The concentrations of fentanyl used in this project were higher than seen with clinical use but overlap with post-mortem overdose concentrations. Further, co-expressed long and short isoforms of hERG, proposed to mimic native channels, displayed an increased sensitivity to fentanyl. Although mechanisms of fentanyl-related sudden death need further investigation, blockade of hERG channels may contribute to death for individuals with high-concentration overdose or compromised cardiac repolarization.