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The molecular mechanisms underlying congenital long QT syndrome (LQTS) are now beginning to be understood. New insights into the etiology and therapeutic strategies are emerging from heterologous expression studies of LQTS-linked mutant proteins, as well as inducible pluripotent stem cell derived cardiomyocytes (iPSC-CMs) from LQTS patients. This review focuses on the major molecular mechanism that underlies LQTS type 2 (LQT2). LQT2 is caused by loss of function (LOF) mutations in KCNH2 (also known as the human Ether-à-go-go-Related Gene or hERG ). Most LQT2-linked mutations are missense mutations and functional studies suggest that ~90% of them disrupt the intracellular transport (trafficking) of KCNH2 -encoded Kv11.1 proteins to the cell membrane. Trafficking deficient LQT2 mutations disrupt Kv11.1 protein folding and misfolded Kv11.1 proteins are retained in the endoplasmic reticulum (ER) until they are degraded in the ER associated degradation pathway (ERAD). This review focuses on the quality control mechanisms in the ER that contribute to the folding and ERAD of Kv11.1 proteins; the mechanism for ER export of Kv11.1 proteins in the secretory pathway; different subclasses of trafficking deficient LQT2 mutations; and strategies being developed to mitigate or correct trafficking deficient LQT2-related phenotypes. [ABSTRACT FROM AUTHOR]

β-Blockers are widely used in the treatment of cardiovascular diseases. However, their effects on HERG channels at comparable conditions remain to be defined. We investigated the direct acute effects of β-blockers on HERG current and the molecular basis of drug binding to HERG channels with mutations of putative common binding site (Y652A and F656C).β-Blockers were selected based on the receptor subtype. Wild-type, Y652A and F656C mutants of HERG channel were stably expressed in HEK293 cells, and the current was recorded by using whole-cell patch-clamp technique (23°C).Carvedilol (nonselective), propranolol (nonselective) and ICI 118551 (β2-selective) inhibited HERG current in a concentration-dependent manner (IC50 0.51, 3.9 and 9.2 μM, respectively). The IC50 value for carvedilol was a clinically relevant concentration. High metoprolol (β1-selective) concentrations were required for blockade (IC50 145 μM), and atenolol (β1-selective) did not inhibit the HERG current.Inhibition of HERG current by carvedilol, propranolol and ICI 118551 was partially but significantly attenuated in Y652A and F656C mutant channels. Affinities of metoprolol to Y652A and F656C mutant channels were not different compared with the wild-type.HERG current block by all β-blockers was not frequency-dependent.Drug affinities to HERG channels were different in β-blockers. Our results provide additional strategies for clinical usage of β-blockers. Atenolol and metoprolol may be preferable for patients with type 1 and 2 long QT syndrome. Carvedilol has a class III antiarrhythmic effect, which may provide the rationale for a favourable clinical outcome compared with other β-blockers as suggested in the recent COMET (Carvedilol Or Metoprolol European Trial) substudy.British Journal of Pharmacology (2006) 147, 642–652. doi:10.1038/sj.bjp.0706508; published online 28 November 2005 [ABSTRACT FROM AUTHOR]

1. Miconazole, an imidazole antifungal agent, is associated with acquired long QT syndrome and ventricular arrhythmias. Miconazole increases the plasma concentration of QT-prolonging drugs by inhibiting the hepatic cytochrome P450 metabolic pathway, but whether it has direct effects on cardiac ion channels has not been elucidated. 2. To determine the mechanism underlying these clinical findings, we investigated the effect of miconazole on human ether-a-go-go-related gene (HERG) K+ channels. 3. HERG channels were heterologously expressed in human embryonic kidney 293 (HEK293) cells and whole-cell currents were recorded using a patch-clamp technique (23 degrees C). 4. Miconazole inhibited HERG peak tail current in a concentration-dependent manner (0.4-40 microM) with an IC50 of 2.1 microM (n=3-5 cells at each concentration, Hill coefficient 1.2). HERG block was not frequency-dependent. It required channel activation, occurred rapidly, and had very slow dissociation properties. 5. The activation curve was shifted in a negative direction (V(1/2): -9.5+/-2.3 mV in controls and -15.3+/-2.4 mV after 4 microM miconazole, P<0.05, n=6). Miconazole did not change other channel kinetics (activation, deactivation, onset of inactivation, recovery from inactivation, steady-state inactivation). 6. The S6 domain mutation, F656C, abolished the inhibitory action of miconazole on HERG current indicating that miconazole preferentially binds to an aromatic amino-acid residue within the pore-S6 region. 7. Our findings indicate that miconazole causes HERG channel block by binding to a common drug receptor, and this involves preferential binding to activated channels. Thus, miconazole prolongs the QT interval by direct inhibition of HERG channels. [ABSTRACT FROM AUTHOR]

LQT2 is one form of the congenital long QT syndrome. It results from mutations in the human ether-a-go-go-related gene (HERG), and more than 80 mutations, usually causing single amino acid substitutions in the HERG protein, are known. HERG encodes the ion channel pore-forming subunit protein for the rapidly activating delayed rectifier K+ channel (IKr) in the heart. This review summarizes current findings about mutations causing LQT2, the mechanisms by which mutations may cause the clinical phenotype of a reduction in IKr and a prolonged QT interval, and how this may be involved in the generation of ventricular arrhythmias. [ABSTRACT FROM AUTHOR]

Droperidol Blocks Cardiac IKr. Introduction: Torsades de pointes have been observed during treatment with droperidol, a butyrophenone neuroleptic agent. Our objectives were (1) to characterize the effects of droperidol on cardiac repolarization and (2) to evaluate effects of droperidol on a major time-dependent outward potassium current involved in cardiac repolarization (IKr). Methods and Results: Isolated, buffer-perfused guinea pig hearts (n = 32) were stimulated at different pacing cycle lengths (150 to 250 msec) and exposed to droperidol in concentrations ranging from 10 to 300 nmol/L. Droperidol increased monophasic action potential duration measured at 90% repolartzation (MAPD90) in a concentration-dependent manner by 9.8 ± 2.3 msec (7.3% ± 0.7%) at 10 nmol/L but by 32.7 ± 3.6 msec (25.7% ± 2.2%) at 300 nmol/L (250-msec cycle length). Increase in MAPD90 also was reverse frequency dependent. As noted previously, droperidol 300 nmol/L increased MAPD90 by 32.7 ± 3.6 msec (25.7% ± 2.2%) at a pacing cycle length of 250 msec but by only 14.1 ± 13 msec (13.6% ± 2.3%) at a pacing cycle length of 150 msec. Patch clamp experiments performed in isolated guinea pig ventricular myocytes demonstrated that droperidol decreases the time-dependent outward K+ current elicited by short depolarizations (250 msec; IK250) in a concentration-dependent manner. Estimated IC50 for IK250, which mostly underlies IKr, was 28 nmol/L. Finally, HERG K+ current elicited in HEK293 cells expressing high levels of HERG protein was decreased 50% by droperidol 322 nmol/L. Conclusion: Potent block of IKr by droperidol is likely to underlie QT prolongation observed in patients treated at therapeutic plasma concentrations (10 to 400 nmol/L) of the drug. [ABSTRACT FROM AUTHOR]

Electrophysiologic Effects of Astemizole Metabolites. Introduction: The selective H1-receptor antagonist astemizole (Hismanal) causes acquired long QT syndrome. Astemizole blocks the rapidly activating delayed rectifier K+current IKr and the human ether-a go-go related gene (HERG) K+ channels that underlie it. Astemizole also is rapidly metabolized. The principal metabolite is desmethylastemizole, which retains H1-receptor antagonist properties, has a long elimination time of 9 to 13 days, and its steady-state serum concentration exceeds that of astemizole by more than 30-fold. A second metabolite is norastemizole, which appears In serum in low concentrations following astemizole ingestion and has undergone development as a new antihistamine drug. Our objective in the present work was to study the effects of desmethylastemizole, norastemizole, and astemizole on HERG K+ channels. Methods and Results: HERG channels were expressed in a mammalian (HEK 293) cell line and studied using the patch clamp technique. Desmethylastemizole and astemizole blocked HERG current with similar concentration dependence (half-maximal block of 1.0 and 0.9 nM, respectively) and block was use dependent Norastemizole also blocked HERG current; however, block was Incomplete and required higher drug concentrations (half-maximal block of 27.7 nM). Conclusions: Desmethylastemizole and astemizole cause equipotent block of HERC channels, and these are among the most potent HERG channel antagonists yet studied. Because desmethytastemizole becomes the dominant compound in serum, these findings support the postulate that it becomes the principal cause of long QT syndrome observed in patients following astemizole ingestion. Norastemizole block of HERG channels is weaker; thus, the risk of producing ventricular arrhythmias may be lower. These findings underscore the potential roles of some H1-receptor antagonist metabolites as K+ channel antagonists. [ABSTRACT FROM AUTHOR]

Early afterdepolarizations (EADs) are a type of bradycardia-dependent triggered activity postulated to cause certain cardiac arrhythmias. The cellular mechanism(s) that underlie EADs have, until recently, remained obscure. Recent evidence has shown that EADs arise from a cellular mechanism rather than cell-to-cell interactions. At least two types of EADs exist that appear to be separable by voltage- (and time-) dependent properties. EADs (hat arise near action potential plateau voltages depend critically on L-type Ca2+ current for depolarization. Studies of Ca2+ currents in single heart cells have provided a basis for explaining the potential roles of L- and T-type Ca2+ currents in EADs. [ABSTRACT FROM AUTHOR]

Drug induced long QT syndrome (LQTS) can lead to cardiac arrhythmias and sudden death, and has emerged as a worldwide problem. Most drugs that cause this are thought to directly block a specific cardiac ion channel (KCNH2 or hERG) that carries the rapidly activating delayed rectifier potassium current, I(Kr). In this issue of the British Journal of Pharmacology, evidence is presented to support a new mechanism for causing drug induced LQTS. The drug pentamidine, at near therapeutic concentrations that do not cause direct KCNH2 channel block, disrupts normal KCNH2 channel protein processing and maturation to reduce its surface membrane expression. This indirect mechanism for reducing I(Kr) is novel, and whether other drugs may cause similar protein trafficking abnormalities is largely unknown. [ABSTRACT FROM AUTHOR]