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New Insights into Cardiac Ion Channel Regulation 3.0

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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 (20 January 2024) | Viewed by 4747

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Special Issue Editors

Dr. Ademuyiwa S. Aromolaran

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Guest Editor

Department of Surgery, Division of Cardiothoracic Surgery, Molecular Medicine Program, 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

Prof. Dr. Brian P. Delisle

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Co-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

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. Ademuyiwa S. Aromolaran
Prof. Dr. Brian P. Delisle
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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.

Related Special Issues

New Insights into Cardiac Ion Channel Regulation in International Journal of Molecular Sciences (10 articles)
New Insights into Cardiac Ion Channel Regulation 2.0 in International Journal of Molecular Sciences (7 articles)

Published Papers (3 papers)

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Research

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22 pages, 5578 KiB

Open AccessArticle

Human Sinoatrial Node Pacemaker Activity: Role of the Slow Component of the Delayed Rectifier K⁺ Current, I_Ks

by Arie O. Verkerk and Ronald Wilders

Int. J. Mol. Sci. 2023, 24(8), 7264; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24087264 - 14 Apr 2023

Cited by 2 | Viewed by 1517

Abstract

The pacemaker activity of the sinoatrial node (SAN) has been studied extensively in animal species but is virtually unexplored in humans. Here we assess the role of the slowly activating component of the delayed rectifier K⁺ current (I_Ks) in human SAN pacemaker activity and its dependence on heart rate and β-adrenergic stimulation. HEK-293 cells were transiently transfected with wild-type KCNQ1 and KCNE1 cDNA, encoding the α- and β-subunits of the I_Ks channel, respectively. KCNQ1/KCNE1 currents were recorded both during a traditional voltage clamp and during an action potential (AP) clamp with human SAN-like APs. Forskolin (10 µmol/L) was used to increase the intracellular cAMP level, thus mimicking β-adrenergic stimulation. The experimentally observed effects were evaluated in the Fabbri–Severi computer model of an isolated human SAN cell. Transfected HEK-293 cells displayed large I_Ks-like outward currents in response to depolarizing voltage clamp steps. Forskolin significantly increased the current density and significantly shifted the half-maximal activation voltage towards more negative potentials. Furthermore, forskolin significantly accelerated activation without affecting the rate of deactivation. During an AP clamp, the KCNQ1/KCNE1 current was substantial during the AP phase, but relatively small during diastolic depolarization. In the presence of forskolin, the KCNQ1/KCNE1 current during both the AP phase and diastolic depolarization increased, resulting in a clearly active KCNQ1/KCNE1 current during diastolic depolarization, particularly at shorter cycle lengths. Computer simulations demonstrated that I_Ks reduces the intrinsic beating rate through its slowing effect on diastolic depolarization at all levels of autonomic tone and that gain-of-function mutations in KCNQ1 may exert a marked bradycardic effect during vagal tone. In conclusion, I_Ks is active during human SAN pacemaker activity and has a strong dependence on heart rate and cAMP level, with a prominent role at all levels of autonomic tone. Full article

(This article belongs to the Special Issue New Insights into Cardiac Ion Channel Regulation 3.0)

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Review

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14 pages, 1863 KiB

Open AccessReview

Impact of Impaired Kidney Function on Arrhythmia-Promoting Cardiac Ion Channel Regulation

by Frederick Sinha, Frank Schweda, Lars S. Maier and Stefan Wagner

Int. J. Mol. Sci. 2023, 24(18), 14198; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241814198 - 17 Sep 2023

Viewed by 1400

Abstract

Chronic kidney disease (CKD) is associated with a significantly increased risk of cardiovascular events and sudden cardiac death. Although arrhythmias are one of the most common causes of sudden cardiac death in CKD patients, the molecular mechanisms involved in the development of arrhythmias are still poorly understood. In this narrative review, therefore, we summarize the current knowledge on the regulation of cardiac ion channels that contribute to arrhythmia in CKD. We do this by first explaining the excitation–contraction coupling, outlining current translational research approaches, then explaining the main characteristics in CKD patients, such as abnormalities in electrolytes and pH, activation of the autonomic nervous system, and the renin–angiotensin–aldosterone system, as well as current evidence for proarrhythmic properties of uremic toxins. Finally, we discuss the substance class of sodium–glucose co-transporter 2 inhibitors (SGLT2i) on their potential to modify cardiac channel regulation in CKD and, therefore, as a treatment option for arrhythmias. Full article

(This article belongs to the Special Issue New Insights into Cardiac Ion Channel Regulation 3.0)

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14 pages, 1557 KiB

Open AccessReview

Relevance of KCNJ5 in Pathologies of Heart Disease

by Karisa M. Meyer, Nipun Malhotra, Jung seo Kwak and Mona El Refaey

Int. J. Mol. Sci. 2023, 24(13), 10849; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241310849 - 29 Jun 2023

Cited by 2 | Viewed by 1193

Abstract

Abnormalities in G-protein-gated inwardly rectifying potassium (GIRK) channels have been implicated in diseased states of the cardiovascular system; however, the role of GIRK4 (Kir3.4) in cardiac physiology and pathophysiology has yet to be completely understood. Within the heart, the K_ACh channel, consisting of two GIRK1 and two GIRK4 subunits, plays a major role in modulating the parasympathetic nervous system’s influence on cardiac physiology. Being that GIRK4 is necessary for the functional K_ACh channel, KCNJ5, which encodes GIRK4, it presents as a therapeutic target for cardiovascular pathology. Human variants in KCNJ5 have been identified in familial hyperaldosteronism type III, long QT syndrome, atrial fibrillation, and sinus node dysfunction. Here, we explore the relevance of KCNJ5 in each of these diseases. Further, we address the limitations and complexities of discerning the role of KCNJ5 in cardiovascular pathophysiology, as identical human variants of KCNJ5 have been identified in several diseases with overlapping pathophysiology. Full article

(This article belongs to the Special Issue New Insights into Cardiac Ion Channel Regulation 3.0)

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