hERG potassium channels are essential for normal electrical activity in the heart. Inherited mutations in the HERG gene cause long QT syndrome, a disorder that predisposes individuals to life-threatening arrhythmias. Arrhythmia can also be induced by a blockage of hERG channels by a surprisingly diverse group of drugs. This side effect is a common reason for drug failure in preclinical safety trials. Insights gained from the crystal structures of other potassium channels have helped our understanding of the block of hERG channels and the mechanisms of gating.

hERG potassium channels and cardiac arrhythmia

Background—Long-QT Syndrome (LQTS) is a cardiovascular disorder characterized by prolongation of the QT interval on ECG and presence of syncope, seizures, and sudden death. Five genes have been imp...

Spectrum of Mutations in Long-QT Syndrome Genes KVLQT1, HERG, SCN5A, KCNE1, and KCNE2

The heart is a rhythmic electromechanical pump, the functioning of which depends on action potential generation and propagation, followed by relaxation and a period of refractoriness until the next...

Molecular Physiology of Cardiac Repolarization

Potassium-selective channels are the largest and most diverse group of ion channels, represented by some 70 known loci in the mammalian genome. The first cloned potassium channel gene was the Drosophila voltage-gated shaker channel, and this was rapidly followed by the identification of other

https://pharmrev.aspetjournals.org/content/pharmrev/57/4/473.full.pdf

International Union of Pharmacology. LIII. Nomenclature and Molecular Relationships of Voltage-Gated Potassium Channels

The human ether-a-go-go related gene (hERG) encodes the pore-forming subunit of the rapid component of the delayed rectifier K+ channel, Kv11.1, which are expressed in the heart, various brain regions, smooth muscle cells, endocrine cells, and a wide range of tumor cell lines. However, it is the role that Kv11.1 channels play in the heart that has been best characterized, for two main reasons. First, it is the gene product involved in chromosome 7-associated long QT syndrome (LQTS), an inherited disorder associated with a markedly increased risk of ventricular arrhythmias and sudden cardiac death. Second, blockade of Kv11.1, by a wide range of prescription medications, causes drug-induced QT prolongation with an increase in risk of sudden cardiac arrest. In the first part of this review, the properties of Kv11.1 channels, including biogenesis, trafficking, gating, and pharmacology are discussed, while the second part focuses on the pathophysiology of Kv11.1 channels.

/pdf/herg-k-channels-structure-function-and-clinical-significance-2jx4nkv4x8.pdf

hERG K+ Channels: Structure, Function, and Clinical Significance

Background—The congenital long-QT syndrome (LQTS) is an inherited disorder characterized by a prolonged cardiac action potential and a QT interval that leads to arrhythmia. Mutations in the human ether-a-go-go–related gene (HERG), which encodes the rapidly activating component of the delayed rectifier current (IKr), cause chromosome 7–linked LQTS (LQT2). Studies of mutant HERG channels in heterologous systems indicate that the mechanisms mediating LQT2 are varied and include mutant subunits that form channels with altered kinetic properties or nonfunctional mutant subunits. We recently reported a novel missense mutation of HERG (G601S) in an LQTS family that we have characterized in the present work. Methods and Results—To elucidate the electrophysiological properties of the G601S mutant channels, we expressed these channels in mammalian cells and Xenopus oocytes. The G601S mutant produced less current than wild-type channels but exhibited no change in kinetic properties or dominant-negative suppression w...

Novel mechanism associated with an inherited cardiac arrhythmia: defective protein trafficking by the mutant HERG (G601S) potassium channel.

We recently performed a detailed anatomicopathologic examination on an aborted human embryo whose mother had taken four tablets of Tedral (one tablet of Tedral contains 130 mg theophylline, 25 mg ephedrine, 8 mg phenobarbital) for an upper respiratory tract infection when the embryo was at approximately 30 days of development. On the same day, the mother developed acute chest pain and a fast, irregular heart beat. The abortion occurred at approximately 80 days of gestation. The heart of the fetus showed truncus arteriosus (Van Praagh type Al). Although no direct cause and effect relationship was proven in this case, the possibility of a teratogenic effect of Tedral during early pregnancy is considered.

An aborted human fetus with truncus arteriosus communis—Possible teratogenic effect of Tedral

Prenalterol (levo-1-[4-hydroxyphenoxy]-3-isopropyl-amino-2-propanol), a new stimulant of cardiac beta-adrenergic receptors in man, induces cardiovascular malformations when topically administered to 2 1/2- through 5 1/2-day chick embryos (Hamburger-Hamilton stages 17-27). Ventricular septal defects (VSD) located in the middle portion of the conal septum and classified as the simple, punched-out type VSD without septal malalignment were the predominant malformations observed throughout the developmental period tested. Arch malformations of the aortic circulation were also observed throughout the test interval, while anomalies of the pulmonary system were observed only at Hamburger-Hamilton stages 17 and 26-27. At stage 25 prenalterol demonstrated an acute toxicity significantly less than (1/50-1/20) epinephrine (P = .035 at concentrations of 8-10 mM) but was relatively equipotent with epinephrine in producing cardiovascular malformations. The effective median concentrations of the two agents were comparable (0.5-1.0 mM). The spectra of malformations induced by prenalterol and epinephrine were qualitatively similar. Malformations included absence of the right and/or left third aortic arch (innominate arteries), persistent remnant of the left fourth aortic arch, and VSD. These results support a previously proposed theory by these investigators that hyperstimulation of cardiac beta-adrenergic receptors in the chick embryo produces cardiovascular malformations.

Cardiovascular malformations associated with administration of prenalterol to young chick embryos

We employed the chick embryo in a comparative study of the effect of Tedral and theophylline on anatomical development. Tedral, which contains theophylline in combination with ephedrine and phenobarbital in the relative dose ratio of theophylline 33: ephedrine 6: phenobarbital 2, or saline for control was dropped onto the surface of the chorioallantoic membrane of 2, 3, 4 and 5-day-old chick embryos. In groups A (theophylline 0.015 M, ephedrine 0.0027 M, phenobarbital 0.0009 M) and B (theophylline 0.011 M, ephedrine 0.0020 M, phenobarbital 0.0007 M), 100% of embryos treated on the 5th day of incubation developed aortic aneurysms with associated cardiovascular malformations. In group C (theophylline 0.005 M, ephedrine 0.0009 M, phenobarbital 0.0003 M), 36.8% of embryos treated on the 5th day of incubation developed aortic aneurysms, and 73.7% of embryos had cardiovascular malformations. These data were compared with those obtained by using theophylline, ephedrine or phenobarbital alone. The commonest cardiovascular anomalies induced by Tedral were double-outlet right ventricle with ventricular septal defect. Aneurysms were larger in size and cardiovascular malformations were more complex in embryos exposed to Tedral than in those treated with theophylline alone. Complex cardiac defects produced by Tedral included transposition of the great arteries, double-outlet right ventricle with double-inlet left ventricle, and truncus arteriosus communis. A slit-like small ventricular septal defect was found in 9.5% of the ephedrine-treated (0.51 mg) chick embryo group and 9.1% in the control embryos. These data show: (1) theophylline, a major component of Tedral, produces cardiovascular anomalies in embryonic chick hearts; (2) there is synergy of all three drugs in Tedral; (3) the specific type of conotruncal defect depends on the timing of administration, e.g., truncus arteriosus communis was produced on day 4 of Tedral administration in chick embryos.

Teratogenic Effect of Tedral (Theophylline, Ephedrine, and Phenobarbital) on Cardiac Development in Chick Embryos

Mitochondrial 16189 DNA Variant and left Ventricular Hypertrophy in Diabetes Mellitus

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