hERG channel trafficking: novel targets in drug-induced long QT syndrome

2007 ◽  
Vol 35 (5) ◽  
pp. 1060-1063 ◽  
Author(s):  
A. Dennis ◽  
L. Wang ◽  
X. Wan ◽  
E. Ficker
Keyword(s):  
Long Qt Syndrome ◽  
Heat Shock Protein 90 ◽  
Delayed Rectifier ◽  
Cardiac Events ◽  
Long Qt ◽  
Drug Induced ◽  
Α Subunit ◽  
Human Cardiomyocytes ◽  
Qt Syndrome ◽  
Therapeutic Compounds

The cardiac potassium channel hERG (human ether-a-go-go-related gene) encodes the α-subunit of the rapid delayed rectifier current IKr in the heart, which contributes to terminal repolarization in human cardiomyocytes. Direct block of hERG/IKr channels by a large number of therapeutic compounds produces acLQTS [acquired LQTS (long QT syndrome)] characterized by drug-induced QT prolongation and torsades de pointes arrhythmias. The cardiotoxicity associated with unintended hERG block has prompted pharmaceutical companies to screen developmental compounds for hERG blockade and made hERG a major target in drug safety programmes. More recently, a novel form of acLQTS has been discovered that may go undetected in most conventional safety assays. Several therapeutic compounds have been identified that reduce hERG/IKr currents not by direct block but by inhibition of hERG/IKr trafficking to the cell surface. Important examples are antineoplastic Hsp90 (heat-shock protein 90) inhibitors such as (i) geldanamycin, (ii) the leukaemia drug arsenic trioxide, (iii) the antiprotozoical pentamidine, (iv) probucol, a cholesterol-lowering drug, and (v) fluoxetine, a widely used antidepressant. Increased awareness of drug-induced hERG trafficking defects will help to further reduce the potentially lethal adverse cardiac events associated with acLQTS.

scholarly journals Slow Delayed Rectifier Potassium Current Blockade Contributes Importantly to Drug-Induced Long QT Syndrome

2013 ◽  
Vol 6 (5) ◽  
pp. 1002-1009 ◽  
Author(s):  
Christiaan C. Veerman ◽  
Arie O. Verkerk ◽  
Marieke T. Blom ◽  
Christine A. Klemens ◽  
Pim N.J. Langendijk ◽  
...  
Keyword(s):  
Long Qt Syndrome ◽  
Potassium Current ◽  
Delayed Rectifier ◽  
Long Qt ◽  
Drug Induced ◽  
Delayed Rectifier Potassium Current ◽  
Qt Syndrome

scholarly journals Risk of drug-induced Long QT Syndrome associated with the use of repurposed COVID-19 drugs: A systematic review

2020 ◽  
Author(s):  
Veronique Michaud ◽  
Pamela Dow ◽  
Sweilem B. Al Rihani ◽  
Malavika Deodhar ◽  
Meghan Arwood ◽  
...  
Keyword(s):  
Long Qt Syndrome ◽  
Qt Interval ◽  
Adverse Event Reporting System ◽  
Torsade De Pointes ◽  
World Health ◽  
Delayed Rectifier ◽  
Long Qt ◽  
Drug Induced ◽  
Repurposed Drugs ◽  
Qt Syndrome

ABSTRACTBackgroundThe World Health Organization first declared SARS-CoV-2 (COVID-19) a pandemic on March 11, 2020. There are currently no vaccines or therapeutic agents proven efficacious to treat COVID-19. So, whether existing approved drugs could be repurposed and used off-label for the treatment of novel COVID-19 disease is being explored.MethodsA thorough literature search was performed to gather information on the pharmacological properties and toxicity of 6 drugs (azithromycin, chloroquine, favipiravir, hydroxychloroquine, lopinavir/ritonavir, remdesivir) proposed to be repurposed to treat COVID-19. Researchers emphasized affinity of these drugs to block the rapid component of the delayed rectifier cardiac potassium current (IKr) encoded by the human ether-a-go-go gene (hERG), their propensity to prolong cardiac repolarization (QT interval) and cause torsade de pointes (TdP). Risk of drug-induced Long QT Syndrome (LQTS) for these drugs was quantified by comparing six indices used to assess such risk and by querying the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System database with specific key words. Data are also provided to compare the level of risk for drug-induced LQTS by these drugs to 23 other, well-recognized, torsadogenic compounds.ResultsEstimators of LQTS risk levels indicated a very-high or high risk for all COVID-19 repurposed drugs except for azithromycin, although cases of TdP have been reported following the administration of this drug. There was an excellent agreement among the various indices used to assess risk of drug-induced LQTS for the six repurposed drugs and the 23 torsadogenic compounds.ConclusionThe risk-benefit assessment for the use of repurposed drugs to treat COVID-19 is complicated since benefits are currently anticipated, not proven. Mandatory monitoring of the QT interval shall be performed as such monitoring is possible for hospitalized patients or by the use of biodevices for outpatients initiated on these drugs.

scholarly journals Suppression-Replacement KCNQ1 Gene Therapy for Type 1 Long QT Syndrome

Circulation ◽  
2021 ◽  
Author(s):  
Steven M. Dotzler ◽  
C.S. John Kim ◽  
William A.C. Gendron ◽  
Wei Zhou ◽  
Dan Ye ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Long Qt Syndrome ◽  
Delayed Rectifier ◽  
Loss Of Function ◽  
Wild Type ◽  
Long Qt ◽  
Α Subunit ◽  
Cardiac Model ◽  
Qt Syndrome

Background: Type 1 long QT syndrome (LQT1) is caused by loss-of-function variants in the KCNQ1 -encoded K v 7.1 potassium channel α-subunit which is essential for cardiac repolarization, providing the slow delayed rectifier current (IKs). No current therapies target the molecular cause of LQT1. Methods: A dual-component "suppression-and-replacement" (SupRep) KCNQ1 gene therapy was created by cloning a KCNQ1 shRNA and a "shRNA-immune" (shIMM) KCNQ1 cDNA modified with silent variants in the shRNA target site, into a single construct. The ability of KCNQ1-SupRep gene therapy to suppress and replace LQT1-causative variants in KCNQ1 was evaluated via heterologous expression in TSA201 cells. For a human in vitro cardiac model, induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) were generated from four patients with LQT1 (KCNQ1-Y171X, -V254M, -I567S, and -A344A/spl) and an unrelated healthy control. CRISPR-Cas9 corrected isogenic control iPSC-CMs were made for two LQT1 lines (correction of KCNQ1-V254M and KCNQ1-A344A/spl). FluoVolt voltage dye was used to measure the cardiac action potential duration (APD) in iPSC-CMs treated with KCNQ1-SupRep. Results: In TSA201 cells, KCNQ1-SupRep achieved mutation-independent suppression of wild-type KCNQ1 and three LQT1-causative variants (KCNQ1-Y171X, -V254M, and -I567S) with simultaneous replacement of KCNQ1-shIMM as measured by allele-specific qRT-PCR and western blot. Using FluoVolt voltage dye to measure the cardiac APD in the four LQT1 patient-derived iPSC-CMs, treatment with KCNQ1-SupRep resulted in shortening of the pathologically prolonged APD at both 90% (APD 90 ) and 50% (APD 50 ) repolarization resulting in APD values similar to those of the two isogenic controls. Conclusions: This study provides the first proof-of-principle gene therapy for complete correction of LQTS. As a dual-component gene therapy vector, KCNQ1-SupRep successfully suppressed and replaced KCNQ1 to normal wild-type levels. In TSA201 cells, co-transfection of LQT1-causative variants and KCNQ1-SupRep caused mutation-independent suppression-and-replacement of KCNQ1 . In LQT1 iPSC-CMs, KCNQ1-SupRep gene therapy shortened the APD, thereby eliminating the pathognomonic feature of LQT1.

scholarly journals Clinical and electrophysiological characterization of a novel mutation (F193L) in the KCNQ1 gene associated with long QT syndrome

2003 ◽  
Vol 104 (4) ◽  
pp. 377-382 ◽  
Author(s):  
Masato YAMAGUCHI ◽  
Masami SHIMIZU ◽  
Hidekazu INO ◽  
Hidenobu TERAI ◽  
Kenshi HAYASHI ◽  
...  
Keyword(s):  
Long Qt Syndrome ◽  
Novel Mutation ◽  
Expression System ◽  
Clinical Manifestations ◽  
Delayed Rectifier ◽  
Polymorphism Analysis ◽  
Long Qt ◽  
Α Subunit ◽  
Kcnq1 Gene ◽  
Qt Syndrome

KCNQ1 is a gene encoding an α subunit of voltage-gated cardiac K+ channels, with properties similar to the slowly activating delayed rectifier K+ current, and one of the genes causing long QT syndrome (LQTS). However, genotype–phenotype correlations of the KCNQ1 gene mutations are not fully understood. The aims of this study were to identify a mutation in the KCNQ1 gene in patients with LQTS, and to characterize the clinical manifestations and electrophysiological properties of the mutation. We screened and identified mutations by PCR, single-strand conformational polymorphism analysis and DNA sequencing. We identified a novel mutation [Phe193Leu (F193L)] in the KCNQ1 gene in one family with LQTS. The patients with this mutation showed a mildly affected phenotype. The proband was a 17-year-old girl who had a prolonged QT interval. Her elder brother, father and paternal grandmother also had the mutation. None of them had any history of syncope. Sudden death was not found in this family. Next, we studied the electrophysiological characteristics of the F193L mutation in the KCNQ1 gene using the expression system in Xenopus oocytes and the two-microelectrode voltage-clamp technique. Co-expression of F193L KCNQ1 with the K+ channel minK suppressed peak (by 23.3%) and tail (by 38.2%) currents compared with those obtained by the combination of wild-type (WT) KCNQ1 and minK. Time constants of current activation in F193L KCNQ1 and F193L KCNQ1+minK were significantly slower than those of WT KCNQ1 and WT KCNQ1+minK. This electrophysiological study indicates that F193L causes less severe KCNQ1 current suppression, and thereby this mutation may result in a mildly affected phenotype.

scholarly journals Elucidating the role of Cavin1 in drug-induced long QT syndrome (diLQTS)

2021 ◽  
Vol 13 (2) ◽  
pp. 228-229
Author(s):  
Z. Al Sayed ◽  
C. Pereira ◽  
C. Jouve ◽  
J. Hulot
Keyword(s):  
Long Qt Syndrome ◽  
Long Qt ◽  
Drug Induced ◽  
Qt Syndrome

scholarly journals Who Is at Risk for Cardiac Events in Young Patients With Long QT Syndrome?

2003 ◽  
Vol 67 (12) ◽  
pp. 1007-1012 ◽  
Author(s):  
Masao Yoshinaga ◽  
Masami Nagashima ◽  
Toshimitsu Shibata ◽  
Ichiro Niimura ◽  
Mitsuo Kitada ◽  
...  
Keyword(s):  
At Risk ◽  
Long Qt Syndrome ◽  
Young Patients ◽  
Cardiac Events ◽  
Long Qt ◽  
Qt Syndrome

scholarly journals Drug-induced long qt syndrome

2020 ◽  
Vol 27 (3) ◽  
pp. 42-52
Author(s):  
G. A. Golovina ◽  
K. V. Zaphiraki ◽  
E. D. Kosmacheva
Keyword(s):  
Long Qt Syndrome ◽  
Qt Interval ◽  
Diagnosis And Treatment ◽  
Fatal Complication ◽  
Long Qt ◽  
Drug Induced ◽  
Long Qt Interval ◽  
Qt Syndrome

In this review drug-induced long QT interval syndrome is described. The authors discuss approaches for the prevention, diagnosis, and treatment of this potentially fatal complication.

scholarly journals Trafficking-deficient hERG K+ channels linked to long QT syndrome are regulated by a microtubule-dependent quality control compartment in the ER

2011 ◽  
Vol 301 (1) ◽  
pp. C75-C85 ◽  
Author(s):  
Jennifer L. Smith ◽  
Christie M. McBride ◽  
Parvathi S. Nataraj ◽  
Daniel C. Bartos ◽  
Craig T. January ◽  
...  
Keyword(s):  
Golgi Apparatus ◽  
Long Qt Syndrome ◽  
Functional Expression ◽  
Delayed Rectifier ◽  
Temperature Sensitive ◽  
Missense Mutations ◽  
Long Qt ◽  
Delayed Rectifier Current ◽  
Golgi Compartment ◽  
Qt Syndrome

The human ether-a-go-go related gene ( hERG) encodes the voltage-gated K+ channel that underlies the rapidly activating delayed-rectifier current in cardiac myocytes. hERG is synthesized in the endoplasmic reticulum (ER) as an “immature” N-linked glycoprotein and is terminally glycosylated in the Golgi apparatus. Most hERG missense mutations linked to long QT syndrome type 2 (LQT2) reduce the terminal glycosylation and functional expression. We tested the hypothesis that a distinct pre-Golgi compartment negatively regulates the trafficking of some LQT2 mutations to the Golgi apparatus. We found that treating cells in nocodazole, a microtubule depolymerizing agent, altered the subcellular localization, functional expression, and glycosylation of the LQT2 mutation G601S-hERG differently from wild-type hERG (WT-hERG). G601S-hERG quickly redistributed to peripheral compartments that partially colocalized with KDEL (Lys-Asp-Glu-Leu) chaperones but not calnexin, Sec31, or the ER golgi intermediate compartment (ERGIC). Treating cells in E-4031, a drug that increases the functional expression of G601S-hERG, prevented the accumulation of G601S-hERG to the peripheral compartments and increased G601S-hERG colocalization with the ERGIC. Coexpressing the temperature-sensitive mutant G protein from vesicular stomatitis virus, a mutant N-linked glycoprotein that is retained in the ER, showed it was not restricted to the same peripheral compartments as G601S-hERG at nonpermissive temperatures. We conclude that the trafficking of G601S-hERG is negatively regulated by a microtubule-dependent compartment within the ER. Identifying mechanisms that prevent the sorting or promote the release of LQT2 channels from this compartment may represent a novel therapeutic strategy for LQT2.

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