scholarly journals ML277 specifically enhances the fully activated open state of KCNQ1 by modulating VSD-pore coupling

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Panpan Hou ◽  
Jingyi Shi ◽  
Kelli McFarland White ◽  
Yuan Gao ◽  
Jianmin Cui
Keyword(s):  
Long Qt Syndrome ◽  
Xenopus Oocytes ◽  
Heart Rhythm ◽  
Long Qt ◽  
Gating Mechanism ◽  
New Strategy ◽  
Pore Opening ◽  
Qt Syndrome ◽  
Voltage Sensing Domain ◽  
Iks Channel

Upon membrane depolarization, the KCNQ1 potassium channel opens at the intermediate (IO) and activated (AO) states of the stepwise voltage-sensing domain (VSD) activation. In the heart, KCNQ1 associates with KCNE1 subunits to form IKs channels that regulate heart rhythm. KCNE1 suppresses the IO state so that the IKs channel opens only to the AO state. Here, we tested modulations of human KCNQ1 channels by an activator ML277 in Xenopus oocytes. It exclusively changes the pore opening properties of the AO state without altering the IO state, but does not affect VSD activation. These observations support a distinctive mechanism responsible for the VSD-pore coupling at the AO state that is sensitive to ML277 modulation. ML277 provides insights and a tool to investigate the gating mechanism of KCNQ1 channels, and our study reveals a new strategy for treating long QT syndrome by specifically enhancing the AO state of native IKs currents.

scholarly journals ML277 specifically enhances pore opening of KCNQ1 with VSD at the activated state by modulating VSD-pore coupling

2019 ◽  
Author(s):  
Panpan Hou ◽  
Jingyi Shi ◽  
Kelli McFarland White ◽  
Yuan Gao ◽  
Jianmin Cui
Keyword(s):  
Voltage Dependence ◽  
Heart Rhythm ◽  
Inactivation Kinetics ◽  
Loss Of Function ◽  
Auxiliary Subunit ◽  
Gating Mechanism ◽  
Activated State ◽  
New Strategy ◽  
Pore Opening ◽  
Voltage Sensing Domain

AbstractIn response to membrane depolarization, the KCNQ1 potassium channel opens at the intermediate (IO) and activated (AO) states that correspond to the stepwise activation of the voltage sensing domain (VSD) to the intermediate (I) and activated (A) states. In the heart, KCNQ1 associates with the auxiliary subunit KCNE1 to form the IKs channel that regulates heart rhythm. More than 300 of loss-of-function KCNQ1 mutations cause long QT syndrome (LQTS). KCNE1 suppresses the IO state so that the IKs channel opens only to the AO state. Thus, enhancing AO state presents a potential therapy for anti-LQTS. Here, we systematically tested modulations of KCNQ1 channels by a KCNQ1 activator, ML277. It enhances the current amplitude, slows down activation, deactivation and inactivation kinetics, shifts the voltage dependence of activation to more positive voltages, decreases the Rb+/K+ permeability ratio, and selectively increases currents of mutant KCNQ1 channels that open only to the AO state. All these observations are consistent with the mechanism that ML277 specifically potentiates the AO state. On the other hand, ML277 does not affect the VSD activation, suggesting that it potentiates the AO state by enhancing the electromechanical (E-M) coupling when the VSD moves to the activated state. Our results suggest that ML277 provides a unique tool to investigate the gating mechanism of KCNQ1 and IKs channels. The specificity of ML277 to increase the AO state of native IKs currents also suggests a new strategy for anti-LQTS therapy.

scholarly journals Fatty acid analogue N-arachidonoyl taurine restores function of IKs channels with diverse long QT mutations

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Sara I Liin ◽  
Johan E Larsson ◽  
Rene Barro-Soria ◽  
Bo Hjorth Bentzen ◽  
H Peter Larsson
Keyword(s):  
Fatty Acid ◽  
Long Qt Syndrome ◽  
Molecular Mechanisms ◽  
Loss Of Function ◽  
Long Qt ◽  
Acid Analogue ◽  
Fatty Acid Analogue ◽  
Qt Syndrome ◽  
Channel Currents ◽  
Iks Channel

About 300 loss-of-function mutations in the IKs channel have been identified in patients with Long QT syndrome and cardiac arrhythmia. How specific mutations cause arrhythmia is largely unknown and there are no approved IKs channel activators for treatment of these arrhythmias. We find that several Long QT syndrome-associated IKs channel mutations shift channel voltage dependence and accelerate channel closing. Voltage-clamp fluorometry experiments and kinetic modeling suggest that similar mutation-induced alterations in IKs channel currents may be caused by different molecular mechanisms. Finally, we find that the fatty acid analogue N-arachidonoyl taurine restores channel gating of many different mutant channels, even though the mutations are in different domains of the IKs channel and affect the channel by different molecular mechanisms. N-arachidonoyl taurine is therefore an interesting prototype compound that may inspire development of future IKs channel activators to treat Long QT syndrome caused by diverse IKs channel mutations.

scholarly journals Clinical, genetic and functional analysis of R562S-Kv7.1 mutation associated with long QT syndrome type 1

EP Europace ◽  
2021 ◽  
Vol 23 (Supplement_3) ◽  
Author(s):  
O Svecova ◽  
R Kula ◽  
L Chmelikova ◽  
J Hosek ◽  
I Synkova ◽  
...  
Keyword(s):  
Long Qt Syndrome ◽  
Adrenergic Stimulation ◽  
Long Qt ◽  
Beta Adrenergic ◽  
The Czech Republic ◽  
Whole Cell Patch Clamp ◽  
Life Threatening ◽  
Qt Syndrome ◽  
Iks Channel

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Ministry of Education, Youth and Sports of the Czech Republic Introduction Loss-of-function variants of the KCNQ1 gene are associated with life-threatening arrhythmogenic long QT syndrome type 1 (LQT1). This gene encodes structure of the slow delayed rectifier potassium channel (IKs). Some functional characteristics of the C-terminal KCNQ1 variant c.1686G > C (p.R562S) have been recently described [1]. However, accumulation of the current under beta-adrenergic stimulation, essential for shortening the action potential duration during exercise, have not been tested. Purpose The aim of this study was to analyse clinical and genetic characteristics of the R562S variant in our patients and to investigate impact of the variant on IKs channel function with a special focus on reactivity of the channels on beta-adrenergic stimulation. Methods The clinical diagnosis was established according to ESC Guidelines including QTc analysis at rest and after exercise. The molecular genetics diagnostics followed according to current practices (the massive parallel sequencing since 2016). The biophysical analysis was performed on Chinese hamster ovary cells (CHO) by the whole cell patch clamp technique at 37 °C. CHO cells were transiently transfected with wild type (WT) and/or R562S human IKs channels (KCNQ1/KCNE1/Yotiao, 1:2:4). Cyclic adenosine monophosphate (cAMP, 200 µM) and okadaic acid (OA, 0.2 µM) in the pipette solution were used to simulate the beta-adrenergic stimulation. In the confocal microscopy experiments, expression of Yotiao was omitted and GFP-tagged KCNQ1 was used. Results The variant R562S-Kv7.1 has been identified in 7 heterozygous carriers from 3 putatively unrelated families in the Czech Republic. The genotype was associated with long QT syndrome phenotype (prolonged QTc, symptoms including syncopes and aborted cardiac arrest) in some of the carriers. The basic functional analysis proved that both homozygous and heterozygous R562S channels are expressed on the cell membrane (confocal microscopy) and carry IKs (whole cell patch clamp) which agrees with the recently published data on this variant. Importantly, reactivity on beta-adrenergic stimulation was absent in both homozygous and heterozygous R562S channels (n = 14 and 8, respectively), but present in the wild-type channels (increase by 51.4 ± 11.1 % at 120-s cAMP/OA diffusion; n = 12). Conclusions The R562S-Kv7.1 variant may be a founder LQT1 variant in our region which will be further investigated in the future. This variant impairs response of IKs channel to beta-adrenergic stimulation. Absence of this essential regulation may considerably aggravate the channel dysfunction and, thus, may result in life-threatening arrhythmias in R562S carriers during exercise.

Abstract 136: Novel Disease Analysis Using Long QT Syndrome-Specific Induced Pluripotent Stem Cells

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Toru Egashira ◽  
Shinsuke Yuasa ◽  
Keiichi Fukuda
Keyword(s):  
Long Qt Syndrome ◽  
Field Potential ◽  
Dominant Negative ◽  
Heterozygous Mutation ◽  
Specific Information ◽  
Long Qt ◽  
Disease Phenotypes ◽  
Severe Arrhythmia ◽  
Qt Syndrome ◽  
Iks Channel

[Background] Although previous reports have indicated that long QT syndrome-specific iPS cells (LQTS-iPSCs)-derived cardiomyocytes recapitulated disease phenotypes, those patients were previously diagnosed with mutated channel profiles. In reality, most patients have no such specific information. To address whether iPSCs could be used for personalized disease characterization, we generated iPSCs from a sporadic LQTS patient with unknown disease cause. [Methods and Results] 1 We generated iPSCs from control (n = 2) and a patient with LQTS, and differentiated into cardiomyocytes through embryoid body (EB) formation. 2 Electrophysiological analysis of the LQTS-iPSCs-derived EBs using multi electrode array system revealed that the duration of the field potential (FPD) was markedly prolonged compared with the control (388.9 ± 44.3 msec vs 202.3 ± 16.3 msec, P<0.01). 3 We tested several drugs affecting QT prolongation to clarify the electrophysiological properties. The IKr blocker E4031 significantly prolonged FPD (% change 1.21 ± 0.02, P<0.01) and induced frequent severe arrhythmia, not only early-after depolarization (n = 8/16 vs n = 1/16) but also torsades de pointes-like arrhythmia, only in LQTS (n = 4/16 vs n = 0/16). The IKs blocker, chromanol 293B did not prolong FPD in LQTS but it significantly prolonged FPD in the control (% change 1.09 ± 0.04, NS vs 1.44 ± 0.07, P<0.01), suggesting the involvement of IKs disturbance in the patient. Isoproterenol induced ventricular tachycardia-like arrhythmia only in LQTS, which was blocked by propranolol. These data strongly suggested a functional impairment in the patient’s IKs channel; genotype analysis for KCNQ1 gene revealed a novel heterozygous mutation, 1893delC. 4 Patch clamp analysis and immunostaining confirmed a dominant-negative role for 1893delC in IKs channel through a trafficking deficiency. [Conclusions] LQTS-iPSCs-derived cardiomyocytes recapitulated the disease phenotypes, and they can be utilized for identification of the disease cause and genotype. This study demonstrated that iPSCs could be useful to characterize the disease, drug responses, diagnosis and genotyping in patients with sporadic LQTS, which in turn may facilitate medical therapies in the clinical settings.

Probucol aggravates long QT syndrome associated with a novel missense mutation M124T in the N-terminus of HERG

2004 ◽  
Vol 107 (2) ◽  
pp. 175-182 ◽  
Author(s):  
Kenshi HAYASHI ◽  
Masami SHIMIZU ◽  
Hidekazu INO ◽  
Masato YAMAGUCHI ◽  
Hidenobu TERAI ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Long Qt Syndrome ◽  
Xenopus Oocytes ◽  
Torsade De Pointes ◽  
Qt Prolongation ◽  
Delayed Rectifier ◽  
Long Qt ◽  
N Terminus ◽  
Qt Syndrome ◽  
Herg Channels

Patients with LQTS (long QT syndrome) with a mutation in a cardiac ion channel gene, leading to mild-to-moderate channel dysfunction, may manifest marked QT prolongation or torsade de pointes only upon an additional stressor. A 59-year-old woman had marked QT prolongation and repeated torsade de pointes 3 months after initiation of probucol, a cholesterol-lowering drug. We identified a single base substitution in the HERG gene by genetic analysis. This novel missense mutation is predicted to cause an amino acid substitution of Met124→Thr (M124T) in the N-terminus. Three other relatives with this mutation also had QT prolongation and one of them had a prolonged QT interval and torsade de pointes accompanied by syncope after taking probucol. We expressed wild-type HERG and HERG with M124T in Xenopus oocytes and characterized the electrophysiological properties of these HERG channels and the action of probucol on the channels. Injection of the M124T mutant cRNA into Xenopus oocytes resulted in expression of functional channels with markedly smaller amplitude. In both HERG channels, probucol decreased the amplitude of the HERG tail current, decelerated the rate of channel activation, accelerated the rate of channel deactivation and shifted the reversal potential to a more positive value. The electrophysiological study indicated that QT lengthening and cardiac arrhythmia in the two present patients were due to inhibition of IKr (rapidly activating delayed rectifier K+ current) by probucol, in addition to the significant suppression of HERG current in HERG channels with the M124T mutation.

scholarly journals Long QT syndrome and its role in THE development of severe heart rhythm disturbances and sudden death

2016 ◽  
pp. 13-19
Author(s):  
L. S. Kovalchuk
Keyword(s):  
Sudden Death ◽  
Long Qt Syndrome ◽  
Qt Interval ◽  
Heart Rhythm ◽  
Long Qt ◽  
Intracellular Magnesium ◽  
Qt Syndrome ◽  
Pathologic Physiology

The article presents information from national and foreign sources on the significance of long QT syndrome on the electrocardiogram as a predictor of severe heart rhythm disturbances and sudden death. It considers the pathologic physiology of the present syndrome, the deficiency of intracellular magnesium plays an important part in its mechanism, which determines the therapeutic aspects leading to normalization of the QT interval

Monogenec Arrhythmic Syndromes: From Molecular and Genetic Aspects to Bedside

Acta Naturae ◽  
2016 ◽  
Vol 8 (2) ◽  
pp. 62-74 ◽  
Author(s):  
E. Z. Golukhova ◽  
O. I. Gromova ◽  
R. A. Shomahov ◽  
N. I. Bulaeva ◽  
L. A. Bockeria
Keyword(s):  
Ventricular Tachycardia ◽  
Sudden Cardiac Death ◽  
Ventricular Fibrillation ◽  
Long Qt Syndrome ◽  
Cardiac Death ◽  
Heart Rhythm ◽  
The United States ◽  
Polymorphic Ventricular Tachycardia ◽  
Long Qt ◽  
Qt Syndrome

The abrupt cessation of effective cardiac function that is generally due to heart rhythm disorders can cause sudden and unexpected death at any age and is referred to as a syndrome called sudden cardiac death (SCD). Annually, about 400,000 cases of SCD occur in the United States alone. Less than 5% of the resuscitation techniques are effective. The prevalence of SCD in a population rises with age according to the prevalence of coronary artery disease, which is the most common cause of sudden cardiac arrest. However, there is a peak in SCD incidence for the age below 5 years, which is equal to 17 cases per 100,000 of the population. This peak is due to congenital monogenic arrhythmic canalopathies. Despite their relative rarity, these cases are obviously the most tragic. The immediate causes, or mechanisms, of SCD are comprehensive. Generally, it is arrhythmic death due to ventricular tachyarrythmias - sustained ventricular tachycardia (VT) or ventricular fibrillation (VF). Bradyarrhythmias and pulseless electrical activity account for no more than 40% of all registered cardiac arrests, and they are more often the outcome of the abovementioned arrhythmias. Our current understanding of the mechanisms responsible for SCD has emerged from decades of basic science investigation into the normal electrophysiology of the heart, the molecular physiology of cardiac ion channels, the fundamental cellular and tissue events associated with cardiac arrhythmias, and the molecular genetics of monogenic disorders of the heart rhythm (for example, the long QT syndrome). This review presents an overview of the molecular and genetic basis of SCD in the long QT syndrome, Brugada syndrome, short QT syndrome, catecholaminergic polymorphic ventricular tachycardia and idiopathic ventricular fibrillation, and arrhythmogenic right ventricular dysplasia, and sudden cardiac death prevention strategies by modern techniques (including implantable cardioverter-defibrillator).

scholarly journals Etiology & Management of Long QT Syndrome

2018 ◽  
Author(s):  
Sai Palati ◽  
Rebecca Monastero ◽  
Elizabeth Varghese ◽  
Sahana Pentyala ◽  
Vamiq Mustahsan ◽  
...  
Keyword(s):  
Long Qt Syndrome ◽  
Qt Interval ◽  
Clinical Signs ◽  
Heart Rhythm ◽  
Torsades De Pointes ◽  
Class Iii ◽  
Long Qt ◽  
Ion Flow ◽  
Class Iii Antiarrhythmics ◽  
Qt Syndrome

Long QT Syndrome (LQTS) is a congenital or acquired condition of the heart rhythm which is characterized on an electrocardiogram by a long QT interval and a type of ventricular tachycardia known as Torsades de Pointes (TdP). The pathophysiology of LQTS may be based in either increases in sympathetic activity in the electrical conduction system, or in abnormal ion flow within the heart, which lead to increases in action potential duration and subsequently prolongs the QT interval, causing predisposition to TdP. LQTS can result from inherited genetic mutations but can also be acquired due to medications such as Class I and Class III antiarrhythmics. Treatment for the condition includes beta-blocker medications, sympathetic denervation procedures, and cardioverter-defibrillator implants. LQTS is of particular interest due to its ability to lead to TdP, which can lead to unconsciousness or sudden cardiac death, and because of its typical onset and severity without other clinical signs which often leads to misdiagnosis. Work must be continued to investigate the drugs which can cause the acquired form of this disease, the genetics of the disease, and the best treatment for varying severities of the disease in order to improve patient outcomes.

scholarly journals Congenital Long QT Syndrome in an Infant

2009 ◽  
Vol 9 (1) ◽  
pp. 111-112
Author(s):  
Aris Lacis ◽  
Inga Lace ◽  
Elina Teivane ◽  
Vita Knauere ◽  
Inguna Lubaua ◽  
...  
Keyword(s):  
Sudden Death ◽  
Long Qt Syndrome ◽  
Heart Rhythm ◽  
Torsades De Pointes ◽  
Cardiac Events ◽  
Long Qt ◽  
Heart Rhythm Disorders ◽  
Qt Syndrome ◽  
First Year Of Life ◽  
Congenital Long Qt Syndrome

Congenital Long QT Syndrome in an InfantLong QT syndrome (LQTS) is a disorder of myocardial repolarization characterized by prolonged QT interval on ECG with prevalence close to 1/3000-1/5000. LQTS is characterized by the occurrence of syncopal episodes due to torsades de pointes ventricular tachycardia (VT) and by a high risk for sudden cardiac death among untreated patients (1, 2, 3). In 12% of patients with LQTS, sudden death is the first manifestation of the disease and only in 4% this happens in the first year of life (2). There is consensus that all symptomatic children with LQTS should be treated with β-blockers which are effective in preventing cardiac events and reducing mortality in 70%, but do not protect patients from sudden death completely (1,2,3,4). The prognosis is poor in untreated patients with annual mortality 20% and 10 year mortality up to 50% (1, 2). Here we present a case of relatively rare congenital heart rhythm disorders in an infant which required immediate treatment.

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