Fentanyl-Induced Block of hERG Channels Is Exacerbated by Hypoxia, Hypokalemia, Alkalosis, and the Presence of hERG1b

  title={Fentanyl-Induced Block of hERG Channels Is Exacerbated by Hypoxia, Hypokalemia, Alkalosis, and the Presence of hERG1b},
  author={Jared Tschirhart and Shetuan Zhang},
  journal={Molecular Pharmacology},
  pages={508 - 517}
Human ether-a-go-go–related gene (hERG) encodes the pore-forming subunit of the rapidly activating delayed rectifier potassium current (IKr) 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 (IhERG) at concentrations that… 
Metabolic and electrolyte abnormalities as risk factors in drug-induced long QT syndrome
The clinical occurrence of drug-induced LQTS is discussed in the context of environmental- and disease-related factors as well as the mechanisms by which they contribute to altered hERG potency and proarrhythmic risk.
Unique Pharmacology, Brain Dysfunction, and Therapeutic Advancements for Fentanyl Misuse and Abuse
The abuse potential and unique pharmacology of fentanyl is presented and its potential mechanisms of action are elucidated, including neural circuit dysfunction and neuroinflammation.
Inherited and Acquired Rhythm Disturbances in Sick Sinus Syndrome, Brugada Syndrome, and Atrial Fibrillation: Lessons from Preclinical Modeling
A critical overview is offered on the effective ability of in silico bioinformatic tools, in vivo animal studies, in vitro models to provide insights on human heart rhythm pathophysiology in case of sick sinus syndrome, Brugada syndrome, and atrial fibrillation and advance their safe and successful translation into the cardiology arena.
Editorial: 50 Years of Opioid Research and the International Narcotics Research Conference
This special issue of Molecular Pharmacology celebrates these 50 years of opioid research and the role that the International Narcotics Research Conference has played in driving this research, by bringing together review and original research articles that present historical highlights, the current state of the art, and perspectives on the future of opioids research.


Blockade of the Human Ether A-Go-Go–Related Gene (hERG) Potassium Channel by Fentanyl
Although mechanisms of fentanyl-related sudden death need further investigation, blockade of hERG channels may contribute to the death of individuals with high-concentration overdose or compromised cardiac repolarization.
Proton block of the pore underlies the inhibition of hERG cardiac K+ channels during acidosis.
The data presented demonstrate that, unlike in other voltage-gated potassium (Kv) channels, substitution of individual histidine residues did not abolish the pH dependence of hERG channel conductance, and strongly suggest that extracellular protons inhibit hERG maximal conductance by blocking the external channel pore.
hERG 1b is critical for human cardiac repolarization
It is found that specific knockdown of the 1b subunit using shRNA caused reductions in 1b mRNA, 1b protein levels, and IKr magnitude by roughly one-half, establishing that hERG 1b is critical for normal repolarization and that loss of 1a is proarrhythmic in human cardiac cells.
The Effect of High Extracellular Potassium on IKr Inhibition by Anti-Arrhythmic Agents
Raising the extracellular potassium to 10 mmol/l, HERG block by azimilide, dofetilide, quinidine and sotalol was significantly decreased, while the block by amiodarone was unchanged, and these results further support the unique electrophysiological effect of amodarone.
Molecular Determinants of Cocaine Block of Human Ether-á-go-go-Related Gene Potassium Channels
It is found that there was no correlation between inactivation gating and cocaine block of hERG channels, and mutations in these residues significantly reduced cocaine-induced block, and the hydrophobicity of the residues at position 656 dictated the cocaine sensitivity of the channel.
Extracellular potassium modulation of drug block of IKr. Implications for torsade de pointes and reverse use-dependence.
The increase in drug block with low [K+]o provides a mechanism to explain the link between hypokalemia and torsade de pointes, with substantial clinical implications.
Hypoxia reduces mature hERG channels through calpain up‐regulation
  • S. Lamothe, Wonju Song, Shetuan Zhang
  • Biology, Medicine
    FASEB journal : official publication of the Federation of American Societies for Experimental Biology
  • 2017
It is found that hypoxic culture of hERG‐expressing human embryonic kidney (HEK) cells and neonatal rat cardiomyocytes reduced hERG current/IKr and mature ERG channel expression with a concomitant increase in calpain expression.
Extracellular K+ Is a Prerequisite for the Function and Plasma Membrane Stability of HERG Channels
Extracellular K+ is a prerequisite for HERG function and membrane stability and is demonstrated for the first time a direct link between a gating state and the plasma membrane stability of an ion channel, HERG.
Role of the pH in state-dependent blockade of hERG currents
Molecular simulations of dofetilide binding to the previously developed and experimentally validated models of the hERG channel in open and open-inactivated states were combined with voltage-clamp experiments to unravel the mechanism(s) of state-dependent blockade.
Mechanism of block and identification of the verapamil binding domain to HERG potassium channels.
Verapamil enters the cell membrane in the neutral form to act at a site within the pore accessible from the intracellular side of the cell membranes, possibly involving the serine at position 620, and this may contribute to its antiarrhythmic mechanism.