Probing the Contribution of
            <i>I</i>
            <sub>Ks</sub>
            to Canine Ventricular Repolarization

Volders, Paul G.A.; Štengl, Milan; Opstal, Jurren M. van; Gerlach, Uwe; Spätjens, Roel L. H. M. G.; Beekman, Jet D.M.; Sipido, Karin R.; Vos, Marc A.

doi:10.1161/01.cir.0000068344.54010.b3

Cited by 227 publications

(66 citation statements)

References 32 publications

(28 reference statements)

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“…β-AR signalling also influences AP duration (APD) and the relationship between APD and the diastolic interval (restitution). However, the regulation of APD by β-AR signalling is complex; the slowly activating delayed rectifier K + channel (I Ks ) is a substrate for phosphorylation by PKA; in large mammals, but not rats and mice, β-AR stimulation increases I Ks which promotes APD shortening [51,52]. In whole hearts, sympathetic nerve stimulation or addition of β-agonists increases the steepness of the slope of the APD restitution curve and reduces the effective refractory period [24,53].…”

Section: β-Adrenergic Signalling In the Heartmentioning

confidence: 99%

β-Adrenergic modulation of myocardial conduction velocity: Connexins vs. sodium current

Campbell

Johnstone

Baillie

et al. 2014

Journal of Molecular and Cellular Cardiology

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Section: β-Adrenergic Signalling In the Heartmentioning

confidence: 99%

β-Adrenergic modulation of myocardial conduction velocity: Connexins vs. sodium current

Campbell

Johnstone

Baillie

et al. 2014

Journal of Molecular and Cellular Cardiology

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“…Extensive studies have shown that K + channels essential for the cardiac AP repolarization are intricately regulated by β-adrenergic stimulation, and different K + channel I Ks , I Kr , I K1 shows different sensitivity to β-adrenergic stimulation. [28] [26] [25] [10] In all previous studies, however, I Ks , I Kr , I K1 was each recorded from different cells and using different V-clamp conditions (i.e. voltage protocol, ionic composition, Ca 2+ buffering).…”

Section: Introductionmentioning

confidence: 99%

Beta-adrenergic stimulation reverses the I Kr–I Ks dominant pattern during cardiac action potential

Bányász

Jian

Horváth

et al. 2014

Pflugers Arch - Eur J Physiol

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β-adrenergic stimulation differentially modulates different K+ channels and thus fine-tunes cardiac action potential (AP) repolarization. However, it remains unclear how the proportion of IKs, IKr, and IK1 current in the same cell would be altered by β-adrenergic stimulation, which would change the relative contribution of individual K+ current to the total repolarization reserve. In this study we used an innovative AP-clamp Sequential Dissection technique to directly record the dynamic –IKs, IKr, IK1– currents during the AP in guinea pig ventricular myocytes under physiologically relevant conditions. Our data provide quantitative measures of the magnitude and time course of IKs, IKr, IK1 currents in the same cell under its own steady-state AP, in a physiological milieu, and with preserved Ca2+ homeostasis. We found that isoproterenol treatment significantly enhanced IKs, moderately increased IK1, but slightly decreased IKr in a dose-dependent manner. The dominance pattern of the K+ currents was IKr>IK1>IKs at the control condition, but reversed to IKr

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“…1-4 Kv7.1 α subunits tetramerize to form the pore of the slowly activating delayed rectifier K + current (I Ks ) channel complex, and in the human heart, I Ks is upregulated by protein kinase A (PKA) activation to prevent ventricular action potential (AP) prolongation during β-adrenergic stimulation. 5,6 Consequently, many patients with LQT1 tend to experience life-threatening symptoms while exercising or swimming. 7,8 Unfortunately, rendering a diagnosis of LQT1 on the basis of a 12-lead ECG alone presents a significant challenge as an estimated 25% of genotype-positive individuals with LQT1 fail to display an abnormal QTc interval at rest, commonly referred to as a concealed LQT1 phenotype.…”

Section: Introductionmentioning

confidence: 99%

A KCNQ1 mutation contributes to the concealed type 1 long QT phenotype by limiting the Kv7.1 channel conformational changes associated with protein kinase A phosphorylation

et al. 2014

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BACKGROUND Type 1 long QT syndrome (LQT1) is caused by loss-of-function mutations in the KCNQ1-encoded Kv7.1 channel that conducts the slowly activating component of the delayed rectifier K+ current (IKs). Clinically, the diagnosis of LQT1 is complicated by variable phenotypic expressivity, whereby approximately 25% of genotype-positive individuals present with concealed LQT1 (resting corrected QT [QTc] interval ≤ 460 ms). OBJECTIVE To determine whether a specific molecular mechanism contributes to concealed LQT1. METHODS We identified a multigenerational LQT1 family whereby 79% of the patients genotype-positive for p.Ile235Asn-KCNQ1 (I235N-Kv7.1) have concealed LQT1. We assessed the effect I235N-Kv7.1 has on IKs and the ventricular action potential (AP) by using in vitro analysis and computational simulations. RESULTS Clinical data showed that all 10 patients with I235N-Kv7.1 have normal resting QTc intervals but abnormal QTc interval prolongation during the recovery phase of an electrocardiographic treadmill stress test. Voltage-clamping HEK293 cells coexpressing wild-type Kv7.1 and I235N-Kv7.1 (to mimic the patients’ genotypes) showed that I235N-Kv7.1 generated relatively normal functioning Kv7.1 channels but were insensitive to protein kinase A (PKA) activation. Phosphomimetic and quinidine sensitivity studies suggest that I235N-Kv7.1 limits the conformational changes in Kv7.1 channels, which are necessary to upregulate IKs after PKA phosphorylation. Computational ventricular AP simulations predicted that the PKA insensitivity of I235N-Kv7.1 is primarily responsible for prolonging the AP with β-adrenergic stimulation, especially at slower cycle lengths. CONCLUSIONS KCNQ1 mutations that generate relatively normal Kv7.1 channels, but limit the upregulation of IKs by PKA activation, likely contribute to concealed LQT1.

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Probing the Contribution of I _Ks to Canine Ventricular Repolarization

Abstract: Background-In large mammals and humans, the contribution of I Ks to ventricular repolarization is still incompletely understood. Methods and Results-In

Cited by 227 publications

References 32 publications

β-Adrenergic modulation of myocardial conduction velocity: Connexins vs. sodium current

β-Adrenergic modulation of myocardial conduction velocity: Connexins vs. sodium current

Beta-adrenergic stimulation reverses the I Kr–I Ks dominant pattern during cardiac action potential

A KCNQ1 mutation contributes to the concealed type 1 long QT phenotype by limiting the Kv7.1 channel conformational changes associated with protein kinase A phosphorylation

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Probing the Contribution of I Ks to Canine Ventricular Repolarization

Abstract: Background-In large mammals and humans, the contribution of I Ks to ventricular repolarization is still incompletely understood. Methods and Results-In

Cited by 227 publications

References 32 publications

β-Adrenergic modulation of myocardial conduction velocity: Connexins vs. sodium current

β-Adrenergic modulation of myocardial conduction velocity: Connexins vs. sodium current

Beta-adrenergic stimulation reverses the I Kr–I Ks dominant pattern during cardiac action potential

A KCNQ1 mutation contributes to the concealed type 1 long QT phenotype by limiting the Kv7.1 channel conformational changes associated with protein kinase A phosphorylation

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Probing the Contribution of I _Ks to Canine Ventricular Repolarization