Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada.
Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada
Mol Pharmacol. 2020 Oct;98(4):508-517. doi: 10.1124/mol.119.119271. Epub 2020 Apr 22.
Human ether-a-go-go-related gene (hERG) encodes the pore-forming subunit of the rapidly activating delayed rectifier potassium current (I) important for repolarization of cardiac action potentials. Drug-induced disruption of hERG channel function is a main cause of acquired long QT syndrome, which can lead to ventricular arrhythmias and sudden death. Illicit fentanyl use is associated with sudden death. We have demonstrated that fentanyl blocks hERG current (I) at concentrations that overlap with the upper range of postmortem blood concentrations in fentanyl-related deaths. Since fentanyl can cause respiratory depression and electrolyte imbalances, in the present study we investigated whether certain pathologic circumstances exacerbate fentanyl-induced block of I Our results show that chronic hypoxia or hypokalemia additively reduced I with fentanyl. As well, high pH potentiated the fentanyl-mediated block of hERG channels, with an IC at pH 8.4 being 7-fold lower than that at pH 7.4. Furthermore, although the full-length hERG variant, hERG1a, has been widely used to study hERG channels, coexpression with the short variant, hERG1b (which does not produce current when expressed alone), produces functional hERG1a/1b channels, which gate more closely resembling native I Our results showed that fentanyl blocked hERG1a/1b channels with a 3-fold greater potency than hERG1a channels. Thus, in addition to a greater susceptibility due to the presence of hERG1b in the human heart, hERG channel block by fentanyl can be exacerbated by certain conditions, such as hypoxia, hypokalemia, or alkalosis, which may increase the risk of fentanyl-induced ventricular arrhythmias and sudden death. SIGNIFICANCE STATEMENT: This work demonstrates that heterologously expressed human ether a-go-go-related gene (hERG) 1a/1b channels, which more closely resemble rapidly activating delayed rectifier potassium current in the human heart, are blocked by fentanyl with a 3-fold greater potency than the previously studied hERG1a expressed alone. Additionally, chronic hypoxia, hypokalemia, and alkalosis can increase the block of hERG current by fentanyl, potentially increasing the risk of cardiac arrhythmias and sudden death.
人类 ether-a-go-go 相关基因 (hERG) 编码快速激活延迟整流钾电流 (I) 的孔形成亚单位，该电流对于心脏动作电位的复极化很重要。药物引起的 hERG 通道功能障碍是获得性长 QT 综合征的主要原因，可导致室性心律失常和猝死。非法芬太尼的使用与猝死有关。我们已经证明，芬太尼在浓度上阻断 hERG 电流 (I)，该浓度与芬太尼相关死亡的死后血液浓度上限重叠。由于芬太尼可引起呼吸抑制和电解质失衡，因此在本研究中我们研究了某些病理情况是否会加剧芬太尼诱导的 I 阻断。我们的结果表明，慢性缺氧或低钾血症可与芬太尼一起使 I 叠加减少。同样，高 pH 值增强了芬太尼介导的 hERG 通道阻断，在 pH 8.4 时的 IC 比 pH 7.4 时低 7 倍。此外，尽管全长 hERG 变体 hERG1a 已被广泛用于研究 hERG 通道，但与短变体 hERG1b 共表达（单独表达时不产生电流）会产生功能上相似的 hERG1a/1b 通道，该通道门控更接近天然 I。我们的结果表明，芬太尼阻断 hERG1a/1b 通道的效力比 hERG1a 通道高 3 倍。因此，除了由于 hERG1b 在人心肌中的存在而导致更大的易感性外，hERG 通道阻断剂芬太尼还可能因某些条件而加剧，例如缺氧，低钾血症或碱中毒，这可能增加芬太尼诱导的室性心律失常和猝死的风险。意义声明：本工作表明，异源表达的人类 ether a-go-go 相关基因 (hERG) 1a/1b 通道更类似于人心率激活延迟整流钾电流，其被芬太尼阻断的效力比以前研究的单独表达的 hERG1a 高 3 倍。此外，慢性缺氧，低钾血症和碱中毒会增加芬太尼对 hERG 电流的阻断作用，从而增加心律失常和猝死的风险。
