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Cells
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Macromolecular Complexes and the Ionic Bases of Arrhythmogenic Diseases
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Macromolecular Complexes and the Ionic Bases of Arrhythmogenic Diseases

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cells of the Cardiovascular System".

Deadline for manuscript submissions: closed (30 September 2022) | Viewed by 12950

Special Issue Editors

Dr. José Jalife

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Guest Editor
Senior InvestigatorCentro Nacional de Investigaciones Cardiovasculares (CNIC) Carlos IIIMelchor Fernández Almagro, 328029 Madrid, Spain
Dr. Alvaro Macias

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Guest Editor
Centro Nacional de Investigaciones Cardiovasculares (CNIC), Carlos IIIMelchor Fernández Almagro, 328029 Madrid, Spain
Interests: electrophysiology; inheritable cardiac diseases; cardiac arrhythmias; ion channels; molecular biology; cellular biology; pharmacology; animal models; iPSC-CMs
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Ion channels are essential proteins embedded in the membrane of individual cardiomyocytes. Ion channels are crucial for the generation and propagation of the cardiac electrical impulse. Emerging evidence strongly suggests that the normal electrical function of the heart is the result of dynamic interactions of membrane ion channels working in an orchestrated fashion as part of complex molecular networks. Such networks work together with exquisite temporal precision to generate each action potential and contraction. Macromolecular complexes play crucial roles in transcription, translation, oligomerization, trafficking, membrane retention, glycosylation, post-translational modification, turnover, function, and degradation of all cardiac ion channels known to date. In addition, the accurate timing of each cardiac beat and contraction demands comparable precision on the assembly and organization of sodium, calcium, and potassium channel complexes within specific subcellular microdomains, where physical proximity allows for prompt and efficient interaction. Dysfunction of ion channel macromolecular complexes may result in arrhythmias, sudden death, and cardiomyopathies. In this Special Issue of Cells, experts in the field will update the reader on the role of ion channel macromolecular assemblies in normal cardiac electrical function and the mechanisms of arrhythmias leading to sudden cardiac death from the bench to the clinic. The articles will focus on current knowledge, important questions that remain unanswered, and what future research must lie ahead to improve current knowledge and advance therapy for inheritable and acquired ion-channel-related diseases.

Dr. José Jalife
Dr. Álvaro Macias
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • arrhythmias
  • cardiac electrophysiology
  • channelosomes
  • channelopathies
  • protein–protein interactions
  • microdomains
  • ion channel trafficking
  • ion channel targeting
  • ion channel localization
  • ion channel turnover
  • sarcolemma
  • sarcoplasmic reticulum
  • E–C coupling
  • potassium channels
  • calcium channels
  • post-translational modifications
  • phosphorylation
  • glycosylation

Published Papers (5 papers)

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Research

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15 pages, 2093 KiB  
Article
Empagliflozin and Dapagliflozin Increase Na+ and Inward Rectifier K+ Current Densities in Human Cardiomyocytes Derived from Induced Pluripotent Stem Cells (hiPSC-CMs)
by María Dago, Teresa Crespo-García, Anabel Cámara-Checa, Josu Rapún, Marcos Rubio-Alarcón, María Marín, Juan Tamargo, Ricardo Caballero and Eva Delpón
Cells 2022, 11(23), 3707; https://doi.org/10.3390/cells11233707 - 22 Nov 2022
Cited by 8 | Viewed by 2376
Abstract
Dapagliflozin (dapa) and empagliflozin (empa) are sodium-glucose cotransporter-2 inhibitors (SGLT2is) that reduce morbidity and mortality in heart failure (HF) patients. Sodium and inward rectifier K+ currents (INa and IK1), carried by Nav1.5 and Kir2.1 channels, respectively, are responsible for [...] Read more.
Dapagliflozin (dapa) and empagliflozin (empa) are sodium-glucose cotransporter-2 inhibitors (SGLT2is) that reduce morbidity and mortality in heart failure (HF) patients. Sodium and inward rectifier K+ currents (INa and IK1), carried by Nav1.5 and Kir2.1 channels, respectively, are responsible for cardiac excitability, conduction velocity, and refractoriness. In HF patients, Nav1.5 and Kir2.1 expression are reduced, enhancing risk of arrhythmia. Incubation with dapa or empa (24-h,1 µM) significantly increased INa and IK1 densities recorded in human-induced pluripotent stem cell-cardiomyocytes (hiPSC-CMs) using patch-clamp techniques. Dapa and empa, respectively, shifted to more hyperpolarized potentials the INa activation and inactivation curves. Identical effects were observed in Chinese hamster ovary (CHO) cells that were incubated with dapa or empa and transiently expressed human Nav1.5 channels. Conversely, empa but not dapa significantly increased human Kir2.1 currents in CHO cells. Dapa and empa effects on INa and IK1 were also apparent in Ca-calmodulin kinase II-silenced CHO cells. Cariporide, a Na+/H+ exchanger type 1 (NHE1) inhibitor, did not increase INa or IK1 in hiPSC-CMs. Dapa and empa at therapeutic concentrations increased INa and IK1 in healthy human cardiomyocytes. These SGLT2is could represent a new class of drugs with a novel and long-pursued antiarrhythmic mechanism of action. Full article
(This article belongs to the Special Issue Macromolecular Complexes and the Ionic Bases of Arrhythmogenic Diseases)
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24 pages, 9277 KiB  
Article
Tortuous Cardiac Intercalated Discs Modulate Ephaptic Coupling
by Ena Ivanovic and Jan P. Kucera
Cells 2022, 11(21), 3477; https://doi.org/10.3390/cells11213477 - 2 Nov 2022
Cited by 2 | Viewed by 1493
Abstract
Cardiac ephaptic coupling, a mechanism mediated by negative electric potentials occurring in the narrow intercellular clefts of intercalated discs, can influence action potential propagation by modulating the sodium current. Intercalated discs are highly tortuous due to the mingling of plicate and interplicate regions. [...] Read more.
Cardiac ephaptic coupling, a mechanism mediated by negative electric potentials occurring in the narrow intercellular clefts of intercalated discs, can influence action potential propagation by modulating the sodium current. Intercalated discs are highly tortuous due to the mingling of plicate and interplicate regions. To investigate the effect of their convoluted structure on ephaptic coupling, we refined our previous model of an intercalated disc and tested predefined folded geometries, which we parametrized by orientation, amplitude and number of folds. Ephaptic interactions (assessed by the minimal cleft potential and amplitude of the sodium currents) were reinforced by concentric folds. With increasing amplitude and number of concentric folds, the cleft potential became more negative during the sodium current transient. This is explained by the larger resistance between the cleft and the bulk extracellular space. In contrast, radial folds attenuated ephaptic interactions and led to a less negative cleft potential due to a decreased net cleft resistance. In conclusion, despite limitations inherent to the simplified geometries and sodium channel distributions investigated as well as simplifications regarding ion concentration changes, these results indicate that the folding pattern of intercalated discs modulates ephaptic coupling. Full article
(This article belongs to the Special Issue Macromolecular Complexes and the Ionic Bases of Arrhythmogenic Diseases)
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20 pages, 3442 KiB  
Article
Altered Expression of Zonula occludens-1 Affects Cardiac Na+ Channels and Increases Susceptibility to Ventricular Arrhythmias
by Mona El Refaey, Sara Coles, Hassan Musa, Tyler L. Stevens, Michael J. Wallace, Nathaniel P. Murphy, Steve Antwi-Boasiako, Lindsay J. Young, Heather R. Manring, Jerry Curran, Michael A. Makara, Kelli Sas, Mei Han, Sara N. Koenig, Michel Skaf, Crystal F. Kline, Paul M. L. Janssen, Federica Accornero, Maegen A. Borzok and Peter J. Mohler
Cells 2022, 11(4), 665; https://doi.org/10.3390/cells11040665 - 14 Feb 2022
Cited by 4 | Viewed by 2926
Abstract
Zonula occludens-1 (ZO-1) is an intracellular scaffolding protein that orchestrates the anchoring of membrane proteins to the cytoskeleton in epithelial and specialized tissue including the heart. There is clear evidence to support the central role of intracellular auxiliary proteins in arrhythmogenesis and previous [...] Read more.
Zonula occludens-1 (ZO-1) is an intracellular scaffolding protein that orchestrates the anchoring of membrane proteins to the cytoskeleton in epithelial and specialized tissue including the heart. There is clear evidence to support the central role of intracellular auxiliary proteins in arrhythmogenesis and previous studies have found altered ZO-1 expression associated with atrioventricular conduction abnormalities. Here, using human cardiac tissues, we identified all three isoforms of ZO-1, canonical (Transcript Variant 1, TV1), CRA_e (Transcript Variant 4, TV4), and an additionally expressed (Transcript Variant 3, TV3) in non-failing myocardium. To investigate the role of ZO-1 on ventricular arrhythmogenesis, we generated a haploinsufficient ZO-1 mouse model (ZO-1+/−). ZO-1+/− mice exhibited dysregulated connexin-43 protein expression and localization at the intercalated disc. While ZO-1+/− mice did not display abnormal cardiac function at baseline, adrenergic challenge resulted in rhythm abnormalities, including premature ventricular contractions and bigeminy. At baseline, ventricular myocytes from the ZO-1+/− mice displayed prolonged action potential duration and spontaneous depolarizations, with ZO-1+/− cells displaying frequent unsolicited (non-paced) diastolic depolarizations leading to spontaneous activity with multiple early afterdepolarizations (EADs). Mechanistically, ZO-1 deficient myocytes displayed a reduction in sodium current density (INa) and an increased sensitivity to isoproterenol stimulation. Further, ZO-1 deficient myocytes displayed remodeling in ICa current, likely a compensatory change. Taken together, our data suggest that ZO-1 deficiency results in myocardial substrate susceptible to triggered arrhythmias. Full article
(This article belongs to the Special Issue Macromolecular Complexes and the Ionic Bases of Arrhythmogenic Diseases)
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Review

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9 pages, 1530 KiB  
Review
When the Gates Swing Open Only: Arrhythmia Mutations That Target the Fast Inactivation Gate of Nav1.5
by Tamer M. Gamal El-Din
Cells 2022, 11(23), 3714; https://doi.org/10.3390/cells11233714 - 22 Nov 2022
Cited by 1 | Viewed by 1497
Abstract
Nav1.5 is the main voltage-gated sodium channel found in cardiac muscle, where it facilitates the fast influx of Na+ ions across the cell membrane, resulting in the fast depolarization phase—phase 0 of the cardiac action potential. As a result, it [...] Read more.
Nav1.5 is the main voltage-gated sodium channel found in cardiac muscle, where it facilitates the fast influx of Na+ ions across the cell membrane, resulting in the fast depolarization phase—phase 0 of the cardiac action potential. As a result, it plays a major role in determining the amplitude and the upstroke velocity of the cardiac impulse. Quantitively, cardiac sodium channel activates in less than a millisecond to trigger the cardiac action potential and inactivates within 2–3 ms to facilitate repolarization and return to the resting state in preparation for firing the next action potential. Missense mutations in the gene that encodes Nav1.5 (SCN5A), change these time constants which leads to a wide spectrum of cardiac diseases ranging from long QT syndrome type 3 (LQT3) to sudden cardiac death. In this mini-review I will focus on the missense mutations in the inactivation gate of Nav1.5 that results in arrhythmia, attempting to correlate the location of the missense mutation to their specific phenotype. Full article
(This article belongs to the Special Issue Macromolecular Complexes and the Ionic Bases of Arrhythmogenic Diseases)
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Other

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14 pages, 3143 KiB  
Perspective
Integrative Computational Modeling of Cardiomyocyte Calcium Handling and Cardiac Arrhythmias: Current Status and Future Challenges
by Henry Sutanto and Jordi Heijman
Cells 2022, 11(7), 1090; https://doi.org/10.3390/cells11071090 - 24 Mar 2022
Cited by 12 | Viewed by 3478
Abstract
Cardiomyocyte calcium-handling is the key mediator of cardiac excitation-contraction coupling. In the healthy heart, calcium controls both electrical impulse propagation and myofilament cross-bridge cycling, providing synchronous and adequate contraction of cardiac muscles. However, calcium-handling abnormalities are increasingly implicated as a cause of cardiac [...] Read more.
Cardiomyocyte calcium-handling is the key mediator of cardiac excitation-contraction coupling. In the healthy heart, calcium controls both electrical impulse propagation and myofilament cross-bridge cycling, providing synchronous and adequate contraction of cardiac muscles. However, calcium-handling abnormalities are increasingly implicated as a cause of cardiac arrhythmias. Due to the complex, dynamic and localized interactions between calcium and other molecules within a cardiomyocyte, it remains experimentally challenging to study the exact contributions of calcium-handling abnormalities to arrhythmogenesis. Therefore, multiscale computational modeling is increasingly being used together with laboratory experiments to unravel the exact mechanisms of calcium-mediated arrhythmogenesis. This article describes various examples of how integrative computational modeling makes it possible to unravel the arrhythmogenic consequences of alterations to cardiac calcium handling at subcellular, cellular and tissue levels, and discusses the future challenges on the integration and interpretation of such computational data. Full article
(This article belongs to the Special Issue Macromolecular Complexes and the Ionic Bases of Arrhythmogenic Diseases)
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