Cardiac sodium channel complexes and arrhythmia: structural and functional roles of the β1 and β3 subunits

Salvage, Samantha C.; Jeevaratnam, Kamalan; Huang, Christopher L.‐H.; Jackson, Antony P.

doi:10.1113/jp283085

Cited by 10 publications

(13 citation statements)

References 96 publications

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“…SCN3B encodes a subunit of the cardiac Na + channel that modulates the late Na + current and thus APD. 28 Variable expression thus could contribute to APD heterogeneity. For other ion channels, the distribution was different.…”

Section: Discussionmentioning

confidence: 99%

Heterogeneity of Repolarization and Cell-Cell Variability of Cardiomyocyte Remodeling Within the Myocardial Infarction Border Zone Contribute to Arrhythmia Susceptibility

Amoni

Vermoortele

Ekhteraei-Tousi

et al. 2023

Circ: Arrhythmia and Electrophysiology

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BACKGROUND: After myocardial infarction, the infarct border zone (BZ) is the dominant source of life-threatening arrhythmias, where fibrosis and abnormal repolarization create a substrate for reentry. We examined whether repolarization abnormalities are heterogeneous within the BZ in vivo and could be related to heterogeneous cardiomyocyte remodeling. METHODS: Myocardial infarction was induced in domestic pigs by 120-minute ischemia-reperfusion injury. After 1 month, remodeling was assessed by magnetic resonance imaging, and electroanatomical mapping was performed to determine the spatial distribution of activation-recovery intervals. Cardiomyocytes were isolated and tissue samples collected from the BZ and remote regions. Optical recording allowed assessment of action potential duration (di-8-Anepps, stimulation at 1 Hz, 37 °C) of large cardiomyocyte populations while gene expression in cardiomyocytes was determined by single nuclear RNA sequencing. RESULTS: In vivo, activation-recovery intervals in the BZ tended to be longer than in remote with increased spatial heterogeneity evidenced by a greater local SD (3.5±1.3 ms versus remote: 2.0±0.5 ms, P =0.036, n pigs =5). Increased activation-recovery interval heterogeneity correlated with enhanced arrhythmia susceptibility. Cellular population studies (n cells =635–862 cells per region) demonstrated greater heterogeneity of action potential duration in the BZ (SD, 105.9±17.0 ms versus remote: 73.9±8.6 ms; P =0.001; n pigs =6), which correlated with heterogeneity of activation-recovery interval in vivo. Cell-cell gene expression heterogeneity in the BZ was evidenced by increased Euclidean distances between nuclei of the BZ (12.1 [9.2–15.0] versus 10.6 [7.5–11.6] in remote; P <0.0001). Differentially expressed genes characterizing BZ cardiomyocyte remodeling included hypertrophy-related and ion channel–related genes with high cell-cell variability of expression. These gene expression changes were driven by stress-responsive TFs (transcription factors). In addition, heterogeneity of left ventricular wall thickness was greater in the BZ than in remote. CONCLUSIONS: Heterogeneous cardiomyocyte remodeling in the BZ is driven by uniquely altered gene expression, related to heterogeneity in the local microenvironment, and translates to heterogeneous repolarization and arrhythmia vulnerability in vivo.

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Section: Discussionmentioning

confidence: 99%

Heterogeneity of Repolarization and Cell-Cell Variability of Cardiomyocyte Remodeling Within the Myocardial Infarction Border Zone Contribute to Arrhythmia Susceptibility

Amoni

Vermoortele

Ekhteraei-Tousi

et al. 2023

Circ: Arrhythmia and Electrophysiology

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“…In contrast, cis-Navβ 3 interactions may enhance local clustering of Nav1.5 ( Salvage et al, 2020a ). These may enhance ephaptic cell-to-cell AP conduction at intercalated disc perinexal membranes ( Salvage et al, 2020a ; Salvage et al, 2023 ). Genetic β-subunit mutations produce pro-arrhythmic phenotypes resembling conduction defects shown by Scn5a ± arrhythmic models ( Hakim et al, 2008 ; Hakim et al, 2010 ).…”

Section: Ion Channel Modulation At the Level Of The Cell Membranementioning

confidence: 99%

Cardiac arrhythmogenesis: roles of ion channels and their functional modification

Lei,

Salvage,

Jackson

et al. 2024

Front. Physiol.

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Cardiac arrhythmias cause significant morbidity and mortality and pose a major public health problem. They arise from disruptions in the normally orderly propagation of cardiac electrophysiological activation and recovery through successive cardiomyocytes in the heart. They reflect abnormalities in automaticity, initiation, conduction, or recovery in cardiomyocyte excitation. The latter properties are dependent on surface membrane electrophysiological mechanisms underlying the cardiac action potential. Their disruption results from spatial or temporal instabilities and heterogeneities in the generation and propagation of cellular excitation. These arise from abnormal function in their underlying surface membrane, ion channels, and transporters, as well as the interactions between them. The latter, in turn, form common regulatory targets for the hierarchical network of diverse signaling mechanisms reviewed here. In addition to direct molecular-level pharmacological or physiological actions on these surface membrane biomolecules, accessory, adhesion, signal transduction, and cytoskeletal anchoring proteins modify both their properties and localization. At the cellular level of excitation–contraction coupling processes, Ca2+ homeostatic and phosphorylation processes affect channel activity and membrane excitability directly or through intermediate signaling. Systems-level autonomic cellular signaling exerts both acute channel and longer-term actions on channel expression. Further upstream intermediaries from metabolic changes modulate the channels both themselves and through modifying Ca2+ homeostasis. Finally, longer-term organ-level inflammatory and structural changes, such as fibrotic and hypertrophic remodeling, similarly can influence all these physiological processes with potential pro-arrhythmic consequences. These normal physiological processes may target either individual or groups of ionic channel species and alter with particular pathological conditions. They are also potentially alterable by direct pharmacological action, or effects on longer-term targets modifying protein or cofactor structure, expression, or localization. Their participating specific biomolecules, often clarified in experimental genetically modified models, thus constitute potential therapeutic targets. The insights clarified by the physiological and pharmacological framework outlined here provide a basis for a recent modernized drug classification. Together, they offer a translational framework for current drug understanding. This would facilitate future mechanistically directed therapeutic advances, for which a number of examples are considered here. The latter are potentially useful for treating cardiac, in particular arrhythmic, disease.

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“…Thus, the existing cryo-EM structures may risk deemphasising the full extent of the glycan trees and their structural implications. Herein, the structural effects of glycans are questioned for Nav1.5 and other Nav channel isoforms, with particular emphasis on the positioning of sialic acid residues close to VSDs and the potential for steric clashes between β-subunits and the glycosylated α-subunit (Salvage et al, 2023b(Salvage et al, , 2020a.…”

Section: Introductionmentioning

confidence: 99%

Isoform-specific N-linked glycosylation of voltage-gated sodium channel alpha-subunits alters beta-subunit binding sites

Beaudoin,

Kohli,

Salvage

et al. 2024

Preprint

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Voltage-gated sodium channel beta-subunits (Nav1.1-1.9) initiate and propagate action potentials in neurons and myocytes. The Nav beta-subunits (beta1-4) have been shown to modulate beta-subunit properties. Homo-oligomerization of beta-subunits on neighboring or opposing plasma membranes has been suggested to facilitate cis or trans interactions, respectively. The interactions between several Nav channel isoforms and beta-subunits have been determined using cryogenic electron microscopy (cryo-EM). Interestingly, the Nav cryo-EM structures reveal the presence of N-linked glycosylation sites. However, only the first glycan moieties are typically resolved at each site due to the flexibility of mature glycan trees. Thus, existing cryo-EM structures may risk de-emphasizing the structural implications of glycans on the Nav channels. Herein, molecular modelling and all-atom molecular dynamics simulations were applied to investigate the conformational landscape of N-linked glycans on Nav channel surfaces. The simulations revealed that negatively-charged sialic acid residues of two glycan sites may interact with voltage-sensing domains. Notably, two Nav1.5 isoform-specific glycans extensively cover the alpha-subunit region that, in other Nav channel alpha-subunit isoforms, corresponds to the binding site for the beta1- (and likely beta3-) subunit immunoglobulin (Ig) domain. Nav1.8 contains a unique N-linked glycosylation site that likely prevents its interaction with the beta2 and beta4-subunit Ig domain. These isoform-specific glycans may have evolved to facilitate specific functional interactions, for example by redirecting beta-subunit Ig-domains outwards to permit cis or trans supra-clustering within specialized cellular compartments such as the cardiomyocyte perinexal space. Further experimental work is necessary to validate these predictions.

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Cardiac sodium channel complexes and arrhythmia: structural and functional roles of the β1 and β3 subunits

Abstract: support-information-section).

Cited by 10 publications

References 96 publications

Heterogeneity of Repolarization and Cell-Cell Variability of Cardiomyocyte Remodeling Within the Myocardial Infarction Border Zone Contribute to Arrhythmia Susceptibility

Heterogeneity of Repolarization and Cell-Cell Variability of Cardiomyocyte Remodeling Within the Myocardial Infarction Border Zone Contribute to Arrhythmia Susceptibility

Cardiac arrhythmogenesis: roles of ion channels and their functional modification

Isoform-specific N-linked glycosylation of voltage-gated sodium channel alpha-subunits alters beta-subunit binding sites

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