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New Insights into Cardiac Ion Channel Regulation 2.0
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New Insights into Cardiac Ion Channel Regulation 2.0

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 May 2022) | Viewed by 22117

Special Issue Editors

Prof. Dr. Brian P. Delisle

E-Mail Website
Guest Editor
Department of Physiology, University of Kentucky, Lexington, KY 40536, USA
Interests: genetics; ion channel; protein trafficking; cardiac arrhythmia; chronobiology; protein structure and function
Special Issues, Collections and Topics in MDPI journals
Dr. Ademuyiwa S. Aromolaran

E-Mail Website
Guest Editor
Molecular Medicine Program, Department of Surgery, Division of Cardiothoracic Surgery, Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT 84112, USA
Interests: cardiac electrophysiology; ion channel biophysics; arrhythmias; inflammation and metabolic disorders
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The ordered electrical excitation of the heart coordinates the efficient pumping of blood throughout the body. Cardiac arrhythmias are electrical disturbances that are often the manifestation of drug toxicity or acquired or genetic diseases. Clinicians and scientists collectively work to identify the basis and prevention of different arrhythmogenic mechanisms. Molecular, cellular, animal, and clinical studies have identified several major families of clinically important cardiac ionic currents and their associated genes and proteins. These studies have led to new discoveries in ion channel regulation at the level of gene transcription, mRNA splicing and stability, translation, protein assembly, intracellular transport (trafficking), second messenger modification, and biophysical function. In this Special Issue, we focus on foundational and emerging concepts in cardiac ion channel regulation, with an emphasis on how this information contributes to a better understanding of normal cardiac excitation and arrhythmogenicity.

Dr. Brian P. Delisle
Dr. Ademuyiwa S. Aromolaran
Guest Editors

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Related Special Issues

Published Papers (7 papers)

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Editorial

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3 pages, 197 KiB  
Editorial
New Insights into Cardiac Ion Channel Regulation 2.0
by Brian P. Delisle and Ademuyiwa S. Aromolaran
Int. J. Mol. Sci. 2023, 24(5), 4999; https://doi.org/10.3390/ijms24054999 - 5 Mar 2023
Cited by 2 | Viewed by 1470
Abstract
Sudden cardiac death (SCD) and arrhythmias represent a global public health problem, accounting for 15–20% of all deaths [...] Full article
(This article belongs to the Special Issue New Insights into Cardiac Ion Channel Regulation 2.0)

Research

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14 pages, 6198 KiB  
Article
mTOR Modulation of IKr through hERG1b-Dependent Mechanisms in Lipotoxic Heart
by Kelly A. Aromolaran, Jenny Do, Joyce Bernardi and Ademuyiwa S. Aromolaran
Int. J. Mol. Sci. 2022, 23(15), 8061; https://doi.org/10.3390/ijms23158061 - 22 Jul 2022
Cited by 4 | Viewed by 1677
Abstract
In the atria, the rapid delayed rectifier channel (IKr) is a critical contributor to repolarization. In lipotoxic atria, increased activity of the serine/threonine mammalian target of rapamycin (mTOR) may remodel IKr and predispose patients to arrhythmias. To investigate whether [...] Read more.
In the atria, the rapid delayed rectifier channel (IKr) is a critical contributor to repolarization. In lipotoxic atria, increased activity of the serine/threonine mammalian target of rapamycin (mTOR) may remodel IKr and predispose patients to arrhythmias. To investigate whether mTOR produced defects in IKr channel function (protein expression and gating mechanisms), electrophysiology and biochemical assays in HEK293 cells stably expressing hERG1a/1b, and adult guinea pig atrial myocytes were used. Feeding with the saturated fatty acid palmitic acid high-fat diet (HFD) was used to induce lipotoxicity. Lipotoxicity-challenged HEK293 cells displayed an increased density of hERG1a/1b currents due to a targeted and significant increase in hERG1b protein expression. Furthermore, lipotoxicity significantly slowed the hERG1a/1b inactivation kinetics, while the activation and deactivation remained essentially unchanged. mTOR complex 1 (mTORC1) inhibition with rapamycin (RAP) reversed the increase in hERG1a/1b density and inactivation. Compared to lipotoxic myocytes, RAP-treated cells displayed action potential durations (APDs) and IKr densities similar to those of controls. HFD feeding triggered arrhythmogenic changes (increased the IKr density and shortened the APD) in the atria, but this was not observed in low-fat-fed controls. The data are the first to show the modulation of IKr by mTORC1, possibly through the remodeling of hERG1b, in lipotoxic atrial myocytes. These results offer mechanistic insights with implications for targeted therapeutic options for the therapy of acquired supraventricular arrhythmias in obesity and associated pathologies. Full article
(This article belongs to the Special Issue New Insights into Cardiac Ion Channel Regulation 2.0)
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24 pages, 2875 KiB  
Article
Frequency-Dependent Properties of the Hyperpolarization-Activated Cation Current, If, in Adult Mouse Heart Primary Pacemaker Myocytes
by Wei Hu, Robert B. Clark, Wayne R. Giles, Colleen Kondo and Henggui Zhang
Int. J. Mol. Sci. 2022, 23(8), 4299; https://doi.org/10.3390/ijms23084299 - 13 Apr 2022
Cited by 2 | Viewed by 2705
Abstract
A number of distinct electrophysiological mechanisms that modulate the myogenic spontaneous pacemaker activity in the sinoatrial node (SAN) of the mammalian heart have been investigated extensively. There is agreement that several (3 or 4) different transmembrane ionic current changes (referred to as the [...] Read more.
A number of distinct electrophysiological mechanisms that modulate the myogenic spontaneous pacemaker activity in the sinoatrial node (SAN) of the mammalian heart have been investigated extensively. There is agreement that several (3 or 4) different transmembrane ionic current changes (referred to as the voltage clock) are involved; and that the resulting net current interacts with direct and indirect effects of changes in intracellular Ca2+ (the calcium clock). However, significant uncertainties, and important knowledge gaps, remain concerning the functional roles in SAN spontaneous pacing of many of the individual ion channel- or exchanger-mediated transmembrane current changes. We report results from patch clamp studies and mathematical modeling of the hyperpolarization-activated current, If, in the generation/modulation of the diastolic depolarization, or pacemaker potential, produced by individual myocytes that were enzymatically isolated from the adult mouse sinoatrial node (SAN). Amphotericin-mediated patch microelectrode recordings at 35 °C were made under control conditions and in the presence of 5 or 10 nM isoproterenol (ISO). These sets of results were complemented and integrated with mathematical modeling of the current changes that take place in the range of membrane potentials (−70 to −50 mV), which corresponds to the ‘pacemaker depolarization’ in the adult mouse SAN. Our results reveal a very small, but functionally important, approximately steady-state or time-independent current generated by residual activation of If channels that are expressed in these pacemaker myocytes. Recordings of the pacemaker depolarization and action potential, combined with measurements of changes in If, and the well-known increases in the L-type Ca2+ current, ICaL, demonstrated that ICaL activation, is essential for myogenic pacing. Moreover, after being enhanced (approximately 3-fold) by 5 or 10 nM ISO, ICaL contributes significantly to the positive chronotropic effect. Our mathematical model has been developed in an attempt to better understand the underlying mechanisms for the pacemaker depolarization and action potential in adult mouse SAN myocytes. After being updated with our new experimental data describing If, our simulations reveal a novel functional component of If in adult mouse SAN. Computational work carried out with this model also confirms that in the presence of ISO the residual activation of If and opening of ICaL channels combine to generate a net current change during the slow diastolic depolarization phase that is essential for the observed accelerated pacemaking rate of these SAN myocytes. Full article
(This article belongs to the Special Issue New Insights into Cardiac Ion Channel Regulation 2.0)
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13 pages, 2177 KiB  
Article
Veratridine Can Bind to a Site at the Mouth of the Channel Pore at Human Cardiac Sodium Channel NaV1.5
by Alican Gulsevin, Andrew M. Glazer, Tiffany Shields, Brett M. Kroncke, Dan M. Roden and Jens Meiler
Int. J. Mol. Sci. 2022, 23(4), 2225; https://doi.org/10.3390/ijms23042225 - 17 Feb 2022
Cited by 4 | Viewed by 2943
Abstract
The cardiac sodium ion channel (NaV1.5) is a protein with four domains (DI-DIV), each with six transmembrane segments. Its opening and subsequent inactivation results in the brief rapid influx of Na+ ions resulting in the depolarization of cardiomyocytes. The neurotoxin [...] Read more.
The cardiac sodium ion channel (NaV1.5) is a protein with four domains (DI-DIV), each with six transmembrane segments. Its opening and subsequent inactivation results in the brief rapid influx of Na+ ions resulting in the depolarization of cardiomyocytes. The neurotoxin veratridine (VTD) inhibits NaV1.5 inactivation resulting in longer channel opening times, and potentially fatal action potential prolongation. VTD is predicted to bind at the channel pore, but alternative binding sites have not been ruled out. To determine the binding site of VTD on NaV1.5, we perform docking calculations and high-throughput electrophysiology experiments in the present study. The docking calculations identified two distinct binding regions. The first site was in the pore, close to the binding site of NaV1.4 and NaV1.5 blocking drugs in experimental structures. The second site was at the “mouth” of the pore at the cytosolic side, partly solvent-exposed. Mutations at this site (L409, E417, and I1466) had large effects on VTD binding, while residues deeper in the pore had no effect, consistent with VTD binding at the mouth site. Overall, our results suggest a VTD binding site close to the cytoplasmic mouth of the channel pore. Binding at this alternative site might indicate an allosteric inactivation mechanism for VTD at NaV1.5. Full article
(This article belongs to the Special Issue New Insights into Cardiac Ion Channel Regulation 2.0)
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18 pages, 3165 KiB  
Article
Zfhx3 Transcription Factor Represses the Expression of SCN5A Gene and Decreases Sodium Current Density (INa)
by Marcos Rubio-Alarcón, Anabel Cámara-Checa, María Dago, Teresa Crespo-García, Paloma Nieto-Marín, María Marín, José Luis Merino, Jorge Toquero, Rafael Salguero-Bodes, Juan Tamargo, Jorge Cebrián, Eva Delpón and Ricardo Caballero
Int. J. Mol. Sci. 2021, 22(23), 13031; https://doi.org/10.3390/ijms222313031 - 2 Dec 2021
Cited by 10 | Viewed by 4027
Abstract
The ZFHX3 and SCN5A genes encode the zinc finger homeobox 3 (Zfhx3) transcription factor (TF) and the human cardiac Na+ channel (Nav1.5), respectively. The effects of Zfhx3 on the expression of the Nav1.5 channel, and in cardiac excitability, are currently unknown. Additionally, [...] Read more.
The ZFHX3 and SCN5A genes encode the zinc finger homeobox 3 (Zfhx3) transcription factor (TF) and the human cardiac Na+ channel (Nav1.5), respectively. The effects of Zfhx3 on the expression of the Nav1.5 channel, and in cardiac excitability, are currently unknown. Additionally, we identified three Zfhx3 variants in probands diagnosed with familial atrial fibrillation (p.M1260T) and Brugada Syndrome (p.V949I and p.Q2564R). Here, we analyzed the effects of native (WT) and mutated Zfhx3 on Na+ current (INa) recorded in HL-1 cardiomyocytes. ZFHX3 mRNA can be detected in human atrial and ventricular samples. In HL-1 cardiomyocytes, transfection of Zfhx3 strongly reduced peak INa density, while the silencing of endogenous expression augmented it (from −65.9 ± 8.9 to −104.6 ± 10.8 pA/pF; n ≥ 8, p < 0.05). Zfhx3 significantly reduced the transcriptional activity of human SCN5A, PITX2, TBX5, and NKX25 minimal promoters. Consequently, the mRNA and/or protein expression levels of Nav1.5 and Tbx5 were diminished (n ≥ 6, p < 0.05). Zfhx3 also increased the expression of Nedd4-2 ubiquitin-protein ligase, enhancing Nav1.5 proteasomal degradation. p.V949I, p.M1260T, and p.Q2564R Zfhx3 produced similar effects on INa density and time- and voltage-dependent properties in WT. WT Zfhx3 inhibits INa as a result of a direct repressor effect on the SCN5A promoter, the modulation of Tbx5 increasing on the INa, and the increased expression of Nedd4-2. We propose that this TF participates in the control of cardiac excitability in human adult cardiac tissue. Full article
(This article belongs to the Special Issue New Insights into Cardiac Ion Channel Regulation 2.0)
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15 pages, 3525 KiB  
Article
Macrophage-Dependent Interleukin-6-Production and Inhibition of IK Contributes to Acquired QT Prolongation in Lipotoxic Guinea Pig Heart
by Md. Kamrul Hasan Chowdhury, Laura Martinez-Mateu, Jenny Do, Kelly A. Aromolaran, Javier Saiz and Ademuyiwa S. Aromolaran
Int. J. Mol. Sci. 2021, 22(20), 11249; https://doi.org/10.3390/ijms222011249 - 18 Oct 2021
Cited by 7 | Viewed by 2944
Abstract
In the heart, the delayed rectifier K current, IK, composed of the rapid (IKr) and slow (IKs) components contributes prominently to normal cardiac repolarization. In lipotoxicity, chronic elevation of pro-inflammatory cytokines may remodel IK [...] Read more.
In the heart, the delayed rectifier K current, IK, composed of the rapid (IKr) and slow (IKs) components contributes prominently to normal cardiac repolarization. In lipotoxicity, chronic elevation of pro-inflammatory cytokines may remodel IK, elevating the risk for ventricular arrythmias and sudden cardiac death. We investigated whether and how the pro-inflammatory interleukin-6 altered IK in the heart, using electrophysiology to evaluate changes in IK in adult guinea pig ventricular myocytes. We found that palmitic acid (a potent inducer of lipotoxicity), induced a rapid (~24 h) and significant increase in IL-6 in RAW264.7 cells. PA-diet fed guinea pigs displayed a severely prolonged QT interval when compared to low-fat diet fed controls. Exposure to isoproterenol induced torsade de pointes, and ventricular fibrillation in lipotoxic guinea pigs. Pre-exposure to IL-6 with the soluble IL-6 receptor produced a profound depression of IKr and IKs densities, prolonged action potential duration, and impaired mitochondrial ATP production. Only with the inhibition of IKr did a proarrhythmic phenotype of IKs depression emerge, manifested as a further prolongation of action potential duration and QT interval. Our data offer unique mechanistic insights with implications for pathological QT interval in patients and vulnerability to fatal arrhythmias. Full article
(This article belongs to the Special Issue New Insights into Cardiac Ion Channel Regulation 2.0)
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Review

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45 pages, 2735 KiB  
Review
Genomic and Non-Genomic Regulatory Mechanisms of the Cardiac Sodium Channel in Cardiac Arrhythmias
by Houria Daimi, Estefanía Lozano-Velasco, Amelia Aranega and Diego Franco
Int. J. Mol. Sci. 2022, 23(3), 1381; https://doi.org/10.3390/ijms23031381 - 26 Jan 2022
Cited by 11 | Viewed by 4906
Abstract
Nav1.5 is the predominant cardiac sodium channel subtype, encoded by the SCN5A gene, which is involved in the initiation and conduction of action potentials throughout the heart. Along its biosynthesis process, Nav1.5 undergoes strict genomic and non-genomic regulatory and [...] Read more.
Nav1.5 is the predominant cardiac sodium channel subtype, encoded by the SCN5A gene, which is involved in the initiation and conduction of action potentials throughout the heart. Along its biosynthesis process, Nav1.5 undergoes strict genomic and non-genomic regulatory and quality control steps that allow only newly synthesized channels to reach their final membrane destination and carry out their electrophysiological role. These regulatory pathways are ensured by distinct interacting proteins that accompany the nascent Nav1.5 protein along with different subcellular organelles. Defects on a large number of these pathways have a tremendous impact on Nav1.5 functionality and are thus intimately linked to cardiac arrhythmias. In the present review, we provide current state-of-the-art information on the molecular events that regulate SCN5A/Nav1.5 and the cardiac channelopathies associated with defects in these pathways. Full article
(This article belongs to the Special Issue New Insights into Cardiac Ion Channel Regulation 2.0)
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