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Cells
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Regulation and Function of Cardiac Ion Channels
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Regulation and Function of Cardiac Ion Channels

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

Deadline for manuscript submissions: closed (15 July 2021) | Viewed by 13904

Special Issue Editor

Dr. Coeli M. Lopes

E-Mail Website
Guest Editor
Department of Medicine, Lab Cardiovascular Research Institute (SMD), University of Rochester Medical Center, Rochester, NY, USA
Interests: ion channels; long QT; cell signaling; cardiac arrhythmias
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Precise ion channel function and regulation are necessary for normal cardiac function. Cardiac channel expression, localization, and regulation are fine tuned to modify cardiomyocyte electrical properties to the required needs. Channel dysregulation in response to disease, inherited mutations, drugs, and hormonal imbalances can cause electrocardiogram (ECG) changes leading to cardiac arrhythmias and sudden death.

This Special Issue will focus on novel molecular mechanisms of cardiac ion channel regulation, and will specifically deal with pathological cardiac channel dysregulation and its consequences for cardiac rhythm and arrhythmia susceptibility. Manuscripts dealing with dysregulation due to common and rare genetic variants of ion channels, novel regulatory subunits, and novel mechanims that disrupt channel trafficking, expression, or transcription will be of interest. We will also focus on non-traditional animal, cell, and computational models and new methods for investigating cardiac ion channel dysregulation.

We intend to include in this Special Issue articles that shed light on new avenues to investigate arrhythmogenesis at a molecular and genetic level and highlight new methods that support these investigations.

Dr. Coeli M. Lopes
Guest Editor

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

  • cardiomyocyte
  • channel
  • regulation
  • QT
  • arrhythmia
  • beta-subunits
  • mutations
  • SNP
  • simulation
  • heart failure
  • diabetes
  • QT-prolonging drugs

Published Papers (4 papers)

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Research

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21 pages, 2849 KiB  
Article
Ion Channel Expression and Electrophysiology of Singular Human (Primary and Induced Pluripotent Stem Cell-Derived) Cardiomyocytes
by Christina Schmid, Najah Abi-Gerges, Michael Georg Leitner, Dietmar Zellner and Georg Rast
Cells 2021, 10(12), 3370; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10123370 - 30 Nov 2021
Cited by 9 | Viewed by 2594
Abstract
Subtype-specific human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are promising tools, e.g., to assess the potential of drugs to cause chronotropic effects (nodal hiPSC-CMs), atrial fibrillation (atrial hiPSC-CMs), or ventricular arrhythmias (ventricular hiPSC-CMs). We used single-cell patch-clamp reverse transcriptase-quantitative polymerase chain reaction to [...] Read more.
Subtype-specific human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are promising tools, e.g., to assess the potential of drugs to cause chronotropic effects (nodal hiPSC-CMs), atrial fibrillation (atrial hiPSC-CMs), or ventricular arrhythmias (ventricular hiPSC-CMs). We used single-cell patch-clamp reverse transcriptase-quantitative polymerase chain reaction to clarify the composition of the iCell cardiomyocyte population (Fujifilm Cellular Dynamics, Madison, WI, USA) and to compare it with atrial and ventricular Pluricytes (Ncardia, Charleroi, Belgium) and primary human atrial and ventricular cardiomyocytes. The comparison of beating and non-beating iCell cardiomyocytes did not support the presence of true nodal, atrial, and ventricular cells in this hiPSC-CM population. The comparison of atrial and ventricular Pluricytes with primary human cardiomyocytes showed trends, indicating the potential to derive more subtype-specific hiPSC-CM models using appropriate differentiation protocols. Nevertheless, the single-cell phenotypes of the majority of the hiPSC-CMs showed a combination of attributes which may be interpreted as a mixture of traits of adult cardiomyocyte subtypes: (i) nodal: spontaneous action potentials and high HCN4 expression and (ii) non-nodal: prominent INa-driven fast inward current and high expression of SCN5A. This may hamper the interpretation of the drug effects on parameters depending on a combination of ionic currents, such as beat rate. However, the proven expression of specific ion channels supports the evaluation of the drug effects on ionic currents in a more realistic cardiomyocyte environment than in recombinant non-cardiomyocyte systems. Full article
(This article belongs to the Special Issue Regulation and Function of Cardiac Ion Channels)
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14 pages, 4928 KiB  
Article
Flecainide Paradoxically Activates Cardiac Ryanodine Receptor Channels under Low Activity Conditions: A Potential Pro-Arrhythmic Action
by Samantha C. Salvage, Esther M. Gallant, James A. Fraser, Christopher L.-H. Huang and Angela F. Dulhunty
Cells 2021, 10(8), 2101; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10082101 - 16 Aug 2021
Cited by 11 | Viewed by 2211
Abstract
Cardiac ryanodine receptor (RyR2) mutations are implicated in the potentially fatal catecholaminergic polymorphic ventricular tachycardia (CPVT) and in atrial fibrillation. CPVT has been successfully treated with flecainide monotherapy, with occasional notable exceptions. Reported actions of flecainide on cardiac sodium currents from mice carrying [...] Read more.
Cardiac ryanodine receptor (RyR2) mutations are implicated in the potentially fatal catecholaminergic polymorphic ventricular tachycardia (CPVT) and in atrial fibrillation. CPVT has been successfully treated with flecainide monotherapy, with occasional notable exceptions. Reported actions of flecainide on cardiac sodium currents from mice carrying the pro-arrhythmic homozygotic RyR2-P2328S mutation prompted our explorations of the effects of flecainide on their RyR2 channels. Lipid bilayer electrophysiology techniques demonstrated a novel, paradoxical increase in RyR2 activity. Preceding flecainide exposure, channels were mildly activated by 1 mM luminal Ca2+ and 1 µM cytoplasmic Ca2+, with open probabilities (Po) of 0.03 ± 0.01 (wild type, WT) or 0.096 ± 0.024 (P2328S). Open probability (Po) increased within 0.5 to 3 min of exposure to 0.5 to 5.0 µM cytoplasmic flecainide, then declined with higher concentrations of flecainide. There were no such increases in a subset of high Po channels with Po ≥ 0.08, although Po then declined with ≥5 µM (WT) or ≥50 µM flecainide (P2328S). On average, channels with Po < 0.08 were significantly activated by 0.5 to 10 µM of flecainide (WT) or 0.5 to 50 µM of flecainide (P2328S). These results suggest that flecainide can bind to separate activation and inhibition sites on RyR2, with activation dominating in lower activity channels and inhibition dominating in more active channels. Full article
(This article belongs to the Special Issue Regulation and Function of Cardiac Ion Channels)
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24 pages, 2408 KiB  
Article
Statistical Approach to Incorporating Experimental Variability into a Mathematical Model of the Voltage-Gated Na+ Channel and Human Atrial Action Potential
by Daniel Gratz, Alexander J Winkle, Seth H Weinberg and Thomas J Hund
Cells 2021, 10(6), 1516; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10061516 - 16 Jun 2021
Viewed by 2619
Abstract
The voltage-gated Na+ channel Nav1.5 is critical for normal cardiac myocyte excitability. Mathematical models have been widely used to study Nav1.5 function and link to a range of cardiac arrhythmias. There is growing appreciation for the importance of [...] Read more.
The voltage-gated Na+ channel Nav1.5 is critical for normal cardiac myocyte excitability. Mathematical models have been widely used to study Nav1.5 function and link to a range of cardiac arrhythmias. There is growing appreciation for the importance of incorporating physiological heterogeneity observed even in a healthy population into mathematical models of the cardiac action potential. Here, we apply methods from Bayesian statistics to capture the variability in experimental measurements on human atrial Nav1.5 across experimental protocols and labs. This variability was used to define a physiological distribution for model parameters in a novel model formulation of Nav1.5, which was then incorporated into an existing human atrial action potential model. Model validation was performed by comparing the simulated distribution of action potential upstroke velocity measurements to experimental measurements from several different sources. Going forward, we hope to apply this approach to other major atrial ion channels to create a comprehensive model of the human atrial AP. We anticipate that such a model will be useful for understanding excitability at the population level, including variable drug response and penetrance of variants linked to inherited cardiac arrhythmia syndromes. Full article
(This article belongs to the Special Issue Regulation and Function of Cardiac Ion Channels)
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Review

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23 pages, 1769 KiB  
Review
Multidimensional Regulation of Cardiac Mitochondrial Potassium Channels
by Bogusz Kulawiak, Piotr Bednarczyk and Adam Szewczyk
Cells 2021, 10(6), 1554; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10061554 - 19 Jun 2021
Cited by 18 | Viewed by 5787
Abstract
Mitochondria play a fundamental role in the energetics of cardiac cells. Moreover, mitochondria are involved in cardiac ischemia/reperfusion injury by opening the mitochondrial permeability transition pore which is the major cause of cell death. The preservation of mitochondrial function is an essential component [...] Read more.
Mitochondria play a fundamental role in the energetics of cardiac cells. Moreover, mitochondria are involved in cardiac ischemia/reperfusion injury by opening the mitochondrial permeability transition pore which is the major cause of cell death. The preservation of mitochondrial function is an essential component of the cardioprotective mechanism. The involvement of mitochondrial K+ transport in this complex phenomenon seems to be well established. Several mitochondrial K+ channels in the inner mitochondrial membrane, such as ATP-sensitive, voltage-regulated, calcium-activated and Na+-activated channels, have been discovered. This obliges us to ask the following question: why is the simple potassium ion influx process carried out by several different mitochondrial potassium channels? In this review, we summarize the current knowledge of both the properties of mitochondrial potassium channels in cardiac mitochondria and the current understanding of their multidimensional functional role. We also critically summarize the pharmacological modulation of these proteins within the context of cardiac ischemia/reperfusion injury and cardioprotection. Full article
(This article belongs to the Special Issue Regulation and Function of Cardiac Ion Channels)
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