The voltage-sensing domain of a hERG1 mutant is a cation-selective channel.

A cationic leak current known as an "omega current" may arise from mutations of the first charged residue in the S4 of the voltage sensor domains of sodium and potassium voltage-gated channels. The voltage-sensing domains (VSDs) in these mutated channels act as pores allowing nonspecific passage of cations, such as Li, K, Cs, and guanidinium. Interestingly, no omega currents have been previously detected in the nonswapped voltage-gated potassium channels such as the human-ether-a-go-go-related (hERG1), hyperpolarization-activated cyclic nucleotide-gated, and ether-a-go-go channels.

Assessing hERG1 Blockade from Bayesian Machine-Learning-Optimized Site Identification by Ligand Competitive Saturation Simulations.

Drug-induced cardiotoxicity is a potentially lethal and yet one of the most common side effects with the drugs in clinical use. Most of the drug-induced cardiotoxicity is associated with an off-target pharmacological blockade of K currents carried out by the cardiac Human--Related (hERG1) potassium channel. There is a compulsory preclinical stage safety assessment for the hERG1 blockade for all classes of drugs, which adds substantially to the cost of drug development.

Allosteric Coupling Between Drug Binding and the Aromatic Cassette in the Pore Domain of the hERG1 Channel: Implications for a State-Dependent Blockade.

Human-ether-a-go-go-related channel (hERG1) is the pore-forming domain of the delayed rectifier K channel in the heart which underlies the current. The channel has been extensively studied due to its propensity to bind chemically diverse group of drugs. The subsequent hERG1 block can lead to a prolongation of the QT interval potentially leading to an abnormal cardiac electrical activity.

The Pore-Lipid Interface: Role of Amino-Acid Determinants of Lipophilic Access by Ivabradine to the hERG1 Pore Domain.

Abnormal cardiac electrical activity is a common side effect caused by unintended block of the promiscuous drug target human -related gene (hERG1), the pore-forming domain of the delayed rectifier K channel in the heart. hERG1 block leads to a prolongation of the QT interval, a phase of the cardiac cycle that underlies myocyte repolarization detectable on the electrocardiogram. Even newly released drugs such as heart-rate lowering agent ivabradine block the rapid delayed rectifier current I, prolong action potential duration, and induce potentially lethal arrhythmia known as torsades de pointes.

Lipid roles in hERG function and interactions with drugs.

Human-ether-a-go-go-related channel (hERG) is a voltage gated potassium channel (K11.1) abundantly expressed in heart and brain tissues. In addition to playing an important role in mediation of repolarizing K currents (I) in Action Potential (AP), hERG is notorious for its propensity to interact with various medications.