Insights into Cardiac IKs (KCNQ1/KCNE1) Channels Regulation

Wu, X; Larsson, H. Peter

doi:10.3390/ijms21249440

Cited by 41 publications

(26 citation statements)

References 146 publications

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“…For hERG channels, a bilayer of POPC (palmitoyloleoyl-phosphatidylcholine) (~270 lipids per leaflet) and for KCNQ1 channels a bilayer of POC and PIP2 (phosphatidyl-4,5-bisphosphate; 26 molecules at inner leaflet) was set up using the builder tool of the CHARMM-GUI website [ 34 , 35 ]. Although it is known that the main chains of these channels work together with other accessory proteins (KCNQ1/KCNE1 [ 36 ] and hERG/KCNE2 [ 11 ]), it is also known that the channels formed from the main chain maintain their function of transmitting current [ 11 ]. Due to the latter, and for the sake of simplicity, it was decided to work only with the main chain.…”

Section: Methodsmentioning

confidence: 99%

Structural Modelling of KCNQ1 and KCNH2 Double Mutant Proteins, Identified in Two Severe Long QT Syndrome Cases, Reveals New Insights into Cardiac Channelopathies

Agudelo

Gil‐Quiñones

Fonseca

et al. 2021

IJMS

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Congenital long QT syndrome (LQTS) is a cardiac channelopathy characterized by a prolongation of the QT interval and T-wave abnormalities, caused, in most cases, by mutations in KCNQ1, KCNH2, and SCN5A. Although the predominant pattern of LQTS inheritance is autosomal dominant, compound heterozygous mutations in genes encoding potassium channels have been reported, often with early disease onset and more severe phenotypes. Since the molecular mechanisms underlying severe phenotypes in carriers of compound heterozygous mutations are unknown, it is possible that these compound mutations lead to synergistic or additive alterations to channel structure and function. In this study, all-atom molecular dynamic simulations of KCNQ1 and hERG channels were carried out, including wild-type and channels with compound mutations found in two patients with severe LQTS phenotypes and limited family history of the disease. Because channels can likely incorporate different subunit combinations from different alleles, there are multiple possible configurations of ion channels in LQTS patients. This analysis allowed us to establish the structural impact of different configurations of mutant channels in the activated/open state. Our data suggest that channels with these mutations show moderate changes in folding energy (in most cases of stabilizing character) and changes in channel mobility and volume, differentiating them from each other and from WT. This would indicate possible alterations in K+ ion flow. Hetero-tetrameric mutant channels showed intermediate structural and volume alterations vis-à-vis homo-tetrameric channels. These findings support the hypothesis that hetero-tetrameric channels in patients with compound heterozygous mutations do not necessarily lead to synergistic structural alterations.

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Section: Methodsmentioning

confidence: 99%

Structural Modelling of KCNQ1 and KCNH2 Double Mutant Proteins, Identified in Two Severe Long QT Syndrome Cases, Reveals New Insights into Cardiac Channelopathies

Agudelo

Gil‐Quiñones

Fonseca

et al. 2021

IJMS

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“…The slow-inward potassium current (IKs) conducted by the channel formed by the molecules KCNQ1/KCNE1 is directly modulated by the action of βAR-Gs-PKA, which phosphorylates the complex and increases its activation [ 73 ]. The electrophysiological consequence of this is the shortening of the action potential and enhanced cardiac function.…”

Section: The Molecular Modulation Of Cardiac Electrophysiology By β-Adrenergic Receptorsmentioning

confidence: 99%

Electrophysiological Remodeling: Cardiac T-Tubules and ß-Adrenoceptors

Gorelik

Harding

2021

Cells

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Beta-adrenoceptors (βAR) are often viewed as archetypal G-protein coupled receptors. Over the past fifteen years, investigations in cardiovascular biology have provided remarkable insights into this receptor family. These studies have shifted pharmacological dogma, from one which centralized the receptor to a new focus on structural micro-domains such as caveolae and t-tubules. Important studies have examined, separately, the structural compartmentation of ion channels and βAR. Despite links being assumed, relatively few studies have specifically examined the direct link between structural remodeling and electrical remodeling with a focus on βAR. In this review, we will examine the nature of receptor and ion channel dysfunction on a substrate of cardiomyocyte microdomain remodeling, as well as the likely ramifications for cardiac electrophysiology. We will then discuss the advances in methodologies in this area with a specific focus on super-resolution microscopy, fluorescent imaging, and new approaches involving microdomain specific, polymer-based agonists. The advent of powerful computational modelling approaches has allowed the science to shift from purely empirical work, and may allow future investigations based on prediction. Issues such as the cross-reactivity of receptors and cellular heterogeneity will also be discussed. Finally, we will speculate as to the potential developments within this field over the next ten years.

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“…In human lung cancer cells, KCNQ1 acts to regulate basal cAMP-stimulated Cl − secretion through the cystic fibrosis transmembrane conductance regulator (CFTR) [8,[10][11][12]. In addition, mutations in cardiac KCNQ1 channels account for the most common congenital defects that cause long QT syndrome (LQTS) [13][14][15], which is a heart disorder resulting in cardiac arrhythmias and about 3000 sudden deaths [16,17].…”

Section: Introductionmentioning

confidence: 99%

A Novel Role of Arrhythmia-Related Gene KCNQ1 Revealed by Multi-Omic Analysis: Theragnostic Value and Potential Mechanisms in Lung Adenocarcinoma

Chang

Liu³

et al. 2022

IJMS

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The early diagnosis, prognostic prediction, and personalized therapy of lung adenocarcinoma (LUAD) remains a challenging issue. KCNQ1 (potassium voltage-gated channel subfamily Q Member 1) is implicated in long QT syndrome (LQTS) and cardiac arrhythmia, while its significance in LUAD remains unclear. In this study, we aimed to explore the significance of KCNQ1 in terms of clinical value, tumor immunity, underlying mechanisms, and a precision medicine approach by means of multi-omics analysis. The association of KCNQ1 with LUAD was first explored. Both altered variants and high expression of KCNQ1 in a TCGA-LUAD cohort indicated a favorable outcome. KCNQ1 levels had a negative correlation with tumor proliferation index Ki67 levels. siRNA-knockdown of KCNQ1 promoted the migration ability of lung cancer cells. KCNQ1 levels were decreased in LUAD tissue compared to normal tissue. A receiver operating characteristic (ROC) curve indicated good diagnostic efficiency of KCNQ1. High KCNQ1 is associated with an immunoactive profile of immune infiltration and immunomodulators and is involved in the inhibition of the cell cycle and DNA replication. Lapatinib was identified as a potent drug for LUAD in the context of low KCNQ1. This study unveiled the significance of KCNQ1 in diagnosis and prognosis and provided a corresponding precision medicine strategy for LUAD.

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Insights into Cardiac IKs (KCNQ1/KCNE1) Channels Regulation

Cited by 41 publications

References 146 publications

Structural Modelling of KCNQ1 and KCNH2 Double Mutant Proteins, Identified in Two Severe Long QT Syndrome Cases, Reveals New Insights into Cardiac Channelopathies

Structural Modelling of KCNQ1 and KCNH2 Double Mutant Proteins, Identified in Two Severe Long QT Syndrome Cases, Reveals New Insights into Cardiac Channelopathies

Electrophysiological Remodeling: Cardiac T-Tubules and ß-Adrenoceptors

A Novel Role of Arrhythmia-Related Gene KCNQ1 Revealed by Multi-Omic Analysis: Theragnostic Value and Potential Mechanisms in Lung Adenocarcinoma

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