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Sodium Channel in Cardiovascular Diseases and Health
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Sodium Channel in Cardiovascular Diseases and Health

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 20 February 2025 | Viewed by 2725

Special Issue Editors

Dr. Xiaobo Wu

E-Mail Website
Guest Editor
Fralin Biomedical Research Institute, Virginia Polytechnic Institute and State University, 2 Riverside Circle, Roanoke, VA 24016, USA
Interests: cardiac arrhythmias; electrical coupling; cardiopulmonary resuscitation
Dr. Xianming Lin

E-Mail Website
Guest Editor
Department of Medicine, NYU Grossman School of Medicine, New York, NY 10016, USA
Interests: cardiomyopathy; ion channel; cardiac arrhythmias; pharmacology

Special Issue Information

Dear Colleagues,

Voltage-gated sodium channels play a crucial role in cardiovascular physiology, especially regulating the initiation and propagation of electrical impulses in excitable cells. They are composed of a pore-forming α subunit and two auxiliary β subunits. They are categorized into tetrodotoxin (TTX)-sensitive and TTX-resistant sodium channels. TTX-sensitive solidum channels such as Nav1.1–1.3 and Nav1.6 are commonly located in the brain, while TTX-resistant sodium channels, mainly Nav1.5, are located in the heart. However, in recent years, it has been clear that some TTX-sensitive sodium channels are also located in the heart and play important roles in maintaining normal cardiac electrical propagation. Sodium channels have been involved in many cardiovascular diseases, including heart failure, ischemic heart disease, atrial fibrillation, pulmonary arterial hypertension and inherited cardiac diseases such as Long QT Syndrome and Brugada Syndrome.

This Special Issue of the International Journal of Molecular Sciences aims to provide a comprehensive overview of the current knowledge on sodium channels in cardiovascular disease and new insights into their underlying molecular mechanisms, clinical implications and potential therapeutic strategies in cardiovascular diseases.

Dr. Xiaobo Wu
Dr. Xianming Lin
Guest Editors

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Keywords

  • sodium channels
  • cardiac conduction
  • physiology
  • mechanisms
  • tetrodoxoxin
  • action potential

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Published Papers (2 papers)

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Research

16 pages, 3451 KiB  
Article
Variable Penetrance and Expressivity of a Rare Pore Loss-of-Function Mutation (p.L889V) of Nav1.5 Channels in Three Spanish Families
by María Gallego-Delgado, Anabel Cámara-Checa, Marcos Rubio-Alarcón, David Heredero-Jung, Laura de la Fuente-Blanco, Josu Rapún, Beatriz Plata-Izquierdo, Sara Pérez-Martín, Jorge Cebrián, Lucía Moreno de Redrojo, Belén García-Berrocal, Eva Delpón, Pedro L. Sánchez, Eduardo Villacorta and Ricardo Caballero
Int. J. Mol. Sci. 2024, 25(9), 4686; https://doi.org/10.3390/ijms25094686 - 25 Apr 2024
Viewed by 949
Abstract
A novel rare mutation in the pore region of Nav1.5 channels (p.L889V) has been found in three unrelated Spanish families that produces quite diverse phenotypic manifestations (Brugada syndrome, conduction disease, dilated cardiomyopathy, sinus node dysfunction, etc.) with variable penetrance among families. We clinically [...] Read more.
A novel rare mutation in the pore region of Nav1.5 channels (p.L889V) has been found in three unrelated Spanish families that produces quite diverse phenotypic manifestations (Brugada syndrome, conduction disease, dilated cardiomyopathy, sinus node dysfunction, etc.) with variable penetrance among families. We clinically characterized the carriers and recorded the Na+ current (INa) generated by p.L889V and native (WT) Nav1.5 channels, alone or in combination, to obtain further insight into the genotypic–phenotypic relationships in patients carrying SCN5A mutations and in the molecular determinants of the Nav1.5 channel function. The variant produced a strong dominant negative effect (DNE) since the peak INa generated by p.L889V channels expressed in Chinese hamster ovary cells, either alone (−69.4 ± 9.0 pA/pF) or in combination with WT (−62.2 ± 14.6 pA/pF), was significantly (n ≥ 17, p < 0.05) reduced compared to that generated by WT channels alone (−199.1 ± 44.1 pA/pF). The mutation shifted the voltage dependence of channel activation and inactivation to depolarized potentials, did not modify the density of the late component of INa, slightly decreased the peak window current, accelerated the recovery from fast and slow inactivation, and slowed the induction kinetics of slow inactivation, decreasing the fraction of channels entering this inactivated state. The membrane expression of p.L889V channels was low, and in silico molecular experiments demonstrated profound alterations in the disposition of the pore region of the mutated channels. Despite the mutation producing a marked DNE and reduction in the INa and being located in a critical domain of the channel, its penetrance and expressivity are quite variable among the carriers. Our results reinforce the argument that the incomplete penetrance and phenotypic variability of SCN5A loss-of-function mutations are the result of a combination of multiple factors, making it difficult to predict their expressivity in the carriers despite the combination of clinical, genetic, and functional studies. Full article
(This article belongs to the Special Issue Sodium Channel in Cardiovascular Diseases and Health)
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10 pages, 2331 KiB  
Article
Challenges in Brugada Syndrome Stratification: Investigating SCN5A Mutation Localization and Clinical Phenotypes
by Adriana Tarantino, Giuseppe Ciconte, Andrea Ghiroldi, Flavio Mastrocinque, Emanuele Micaglio, Antonio Boccellino, Gabriele Negro, Marco Piccoli, Federica Cirillo, Gabriele Vicedomini, Vincenzo Santinelli, Luigi Anastasia and Carlo Pappone
Int. J. Mol. Sci. 2023, 24(23), 16658; https://doi.org/10.3390/ijms242316658 - 23 Nov 2023
Cited by 3 | Viewed by 1275
Abstract
Brugada Syndrome (BrS) is a genetic heart condition linked to sudden cardiac death. Though the SCN5A gene is primarily associated with BrS, there is a lack of comprehensive studies exploring the connection between SCN5A mutation locations and the clinical presentations of the syndrome. [...] Read more.
Brugada Syndrome (BrS) is a genetic heart condition linked to sudden cardiac death. Though the SCN5A gene is primarily associated with BrS, there is a lack of comprehensive studies exploring the connection between SCN5A mutation locations and the clinical presentations of the syndrome. This study aimed to address this gap and gain further understanding of the syndrome. The investigation classified 36 high-risk BrS patients based on SCN5A mutations within the transmembrane/structured (TD) and intra-domain loops (IDLs) lacking a 3D structure. We characterized the intrinsically disordered regions (IDRs) abundant in IDLs, using bioinformatics tools to predict IDRs and post-translational modifications (PTMs) in NaV1.5. Interestingly, it was found that current predictive tools often underestimate the impacts of mutations in IDLs and disordered regions. Moreover, patients with SCN5A mutations confined to IDL regions—previously deemed ‘benign’—displayed clinical symptoms similar to those carrying ‘damaging’ variants. Our research illuminates the difficulty in stratifying patients based on SCN5A mutation locations, emphasizing the vital role of IDLs in the NaV1.5 channel’s functioning and protein interactions. We advocate for caution when using predictive tools for mutation evaluation in these regions and call for the development of improved strategies in accurately assessing BrS risk Full article
(This article belongs to the Special Issue Sodium Channel in Cardiovascular Diseases and Health)
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