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20 pages, 1544 KiB

Open AccessArticle

Intracellular Na⁺ Modulates Pacemaking Activity in Murine Sinoatrial Node Myocytes: An In Silico Analysis

by Stefano Morotti, Haibo Ni, Colin H. Peters, Christian Rickert, Ameneh Asgari-Targhi, Daisuke Sato, Alexey V. Glukhov, Catherine Proenza and Eleonora Grandi

Int. J. Mol. Sci. 2021, 22(11), 5645; https://doi.org/10.3390/ijms22115645 - 26 May 2021

Cited by 13 | Viewed by 3079

Abstract

Background: The mechanisms underlying dysfunction in the sinoatrial node (SAN), the heart’s primary pacemaker, are incompletely understood. Electrical and Ca²⁺-handling remodeling have been implicated in SAN dysfunction associated with heart failure, aging, and diabetes. Cardiomyocyte [Na⁺]_i is [...] Read more.

Background: The mechanisms underlying dysfunction in the sinoatrial node (SAN), the heart’s primary pacemaker, are incompletely understood. Electrical and Ca²⁺-handling remodeling have been implicated in SAN dysfunction associated with heart failure, aging, and diabetes. Cardiomyocyte [Na⁺]_i is also elevated in these diseases, where it contributes to arrhythmogenesis. Here, we sought to investigate the largely unexplored role of Na⁺ homeostasis in SAN pacemaking and test whether [Na⁺]_i dysregulation may contribute to SAN dysfunction. Methods: We developed a dataset-specific computational model of the murine SAN myocyte and simulated alterations in the major processes of Na⁺ entry (Na⁺/Ca²⁺ exchanger, NCX) and removal (Na⁺/K⁺ ATPase, NKA). Results: We found that changes in intracellular Na⁺ homeostatic processes dynamically regulate SAN electrophysiology. Mild reductions in NKA and NCX function increase myocyte firing rate, whereas a stronger reduction causes bursting activity and loss of automaticity. These pathologic phenotypes mimic those observed experimentally in NCX- and ankyrin-B-deficient mice due to altered feedback between the Ca²⁺ and membrane potential clocks underlying SAN firing. Conclusions: Our study generates new testable predictions and insight linking Na⁺ homeostasis to Ca²⁺ handling and membrane potential dynamics in SAN myocytes that may advance our understanding of SAN (dys)function. Full article

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

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15 pages, 3154 KiB

Open AccessArticle

Characterization of the HCN Interaction Partner TRIP8b/PEX5R in the Intracardiac Nervous System of TRIP8b-Deficient and Wild-Type Mice

by Katharina Scherschel, Hanna Bräuninger, Andrea Mölders, Nadine Erlenhardt, Ehsan Amin, Christiane Jungen, Ulrike Pape, Diana Lindner, Dane M. Chetkovich, Nikolaj Klöcker and Christian Meyer

Int. J. Mol. Sci. 2021, 22(9), 4772; https://doi.org/10.3390/ijms22094772 - 30 Apr 2021

Cited by 3 | Viewed by 2347

Abstract

The tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b/PEX5R) is an interaction partner and auxiliary subunit of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, which are key for rhythm generation in the brain and in the heart. Since TRIP8b is expressed in central neurons but not in cardiomyocytes, [...] Read more.

The tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b/PEX5R) is an interaction partner and auxiliary subunit of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, which are key for rhythm generation in the brain and in the heart. Since TRIP8b is expressed in central neurons but not in cardiomyocytes, the TRIP8b-HCN interaction has been studied intensely in the brain, but is deemed irrelevant in the cardiac conduction system. Still, to date, TRIP8b has not been studied in the intrinsic cardiac nervous system (ICNS), a neuronal network located within epicardial fat pads. In vitro electrophysiological studies revealed that TRIP8b-deficient mouse hearts exhibit increased atrial refractory and atrioventricular nodal refractory periods, compared to hearts of wild-type littermates. Meanwhile, heart rate, sino-nodal recovery time, and ventricular refractory period did not differ between genotypes. Trip8b mRNA was detected in the ICNS by quantitative polymerase chain reaction. RNAscope in situ hybridization confirmed Trip8b localization in neuronal somata and nerve fibers. Additionally, we found a very low amount of mRNAs in the sinus node and atrioventricular node, most likely attributable to the delicate fibers innervating the conduction system. In contrast, TRIP8b protein was not detectable. Our data suggest that TRIP8b in the ICNS may play a role in the modulation of atrial electrophysiology beyond HCN-mediated sino-nodal control of the heart. Full article

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

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19 pages, 5305 KiB

Open AccessArticle

Physiological Roles of the Rapidly Activated Delayed Rectifier K⁺ Current in Adult Mouse Heart Primary Pacemaker Activity

by Wei Hu, Robert B. Clark, Wayne R. Giles, Erwin Shibata and Henggui Zhang

Int. J. Mol. Sci. 2021, 22(9), 4761; https://doi.org/10.3390/ijms22094761 - 30 Apr 2021

Cited by 5 | Viewed by 2387

Abstract

Robust, spontaneous pacemaker activity originating in the sinoatrial node (SAN) of the heart is essential for cardiovascular function. Anatomical, electrophysiological, and molecular methods as well as mathematical modeling approaches have quite thoroughly characterized the transmembrane fluxes of Na⁺, K⁺ and [...] Read more.

Robust, spontaneous pacemaker activity originating in the sinoatrial node (SAN) of the heart is essential for cardiovascular function. Anatomical, electrophysiological, and molecular methods as well as mathematical modeling approaches have quite thoroughly characterized the transmembrane fluxes of Na⁺, K⁺ and Ca²⁺ that produce SAN action potentials (AP) and ‘pacemaker depolarizations’ in a number of different in vitro adult mammalian heart preparations. Possible ionic mechanisms that are responsible for SAN primary pacemaker activity are described in terms of: (i) a Ca²⁺-regulated mechanism based on a requirement for phasic release of Ca²⁺ from intracellular stores and activation of an inward current-mediated by Na⁺/Ca²⁺ exchange; (ii) time- and voltage-dependent activation of Na⁺ or Ca²⁺ currents, as well as a cyclic nucleotide-activated current, I_f; and/or (iii) a combination of (i) and (ii). Electrophysiological studies of single spontaneously active SAN myocytes in both adult mouse and rabbit hearts consistently reveal significant expression of a rapidly activating time- and voltage-dependent K⁺ current, often denoted I_Kr, that is selectively expressed in the leading or primary pacemaker region of the adult mouse SAN. The main goal of the present study was to examine by combined experimental and simulation approaches the functional or physiological roles of this K⁺ current in the pacemaker activity. Our patch clamp data of mouse SAN myocytes on the effects of a pharmacological blocker, E4031, revealed that a rapidly activating K⁺ current is essential for action potential (AP) repolarization, and its deactivation during the pacemaker potential contributes a small but significant component to the pacemaker depolarization. Mathematical simulations using a murine SAN AP model confirm that well known biophysical properties of a delayed rectifier K⁺ current can contribute to its role in generating spontaneous myogenic activity. Full article

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

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19 pages, 4976 KiB

Open AccessArticle

Deletion of Trpm4 Alters the Function of the Na_v1.5 Channel in Murine Cardiac Myocytes

by Lijo Cherian Ozhathil, Jean-Sébastien Rougier, Prakash Arullampalam, Maria C. Essers, Daniela Ross-Kaschitza and Hugues Abriel

Int. J. Mol. Sci. 2021, 22(7), 3401; https://doi.org/10.3390/ijms22073401 - 26 Mar 2021

Cited by 17 | Viewed by 3241

Abstract

Transient receptor potential melastatin member 4 (TRPM4) encodes a Ca²⁺-activated, non-selective cation channel that is functionally expressed in several tissues, including the heart. Pathogenic mutants in TRPM4 have been reported in patients with inherited cardiac diseases, including conduction blockage and Brugada [...] Read more.

Transient receptor potential melastatin member 4 (TRPM4) encodes a Ca²⁺-activated, non-selective cation channel that is functionally expressed in several tissues, including the heart. Pathogenic mutants in TRPM4 have been reported in patients with inherited cardiac diseases, including conduction blockage and Brugada syndrome. Heterologous expression of mutant channels in cell lines indicates that these mutations can lead to an increase or decrease in TRPM4 expression and function at the cell surface. While the expression and clinical variant studies further stress the importance of TRPM4 in cardiac function, the cardiac electrophysiological phenotypes in Trpm4 knockdown mouse models remain incompletely characterized. To study the functional consequences of Trpm4 deletion on cardiac electrical activity in mice, we performed perforated-patch clamp and immunoblotting studies on isolated atrial and ventricular cardiac myocytes and surfaces, as well as on pseudo- and intracardiac ECGs, either in vivo or in Langendorff-perfused explanted mouse hearts. We observed that TRPM4 is expressed in atrial and ventricular cardiac myocytes and that deletion of Trpm4 unexpectedly reduces the peak Na⁺ currents in myocytes. Hearts from Trpm4^−/− mice presented increased sensitivity towards mexiletine, a Na⁺ channel blocker, and slower intraventricular conduction, consistent with the reduction of the peak Na⁺ current observed in the isolated cardiac myocytes. This study suggests that TRPM4 expression impacts the Na⁺ current in murine cardiac myocytes and points towards a novel function of TRPM4 regulating the Na_v1.5 function in murine cardiac myocytes. Full article

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

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11 pages, 1786 KiB

Open AccessArticle

Regulation of Kv11.1 Isoform Expression by Polyadenylate Binding Protein Nuclear 1

by Matthew R. Stump, Rachel T. Nguyen, Rachel H. Drgastin, Delaney Search, Qiuming Gong and Zhengfeng Zhou

Int. J. Mol. Sci. 2021, 22(2), 863; https://doi.org/10.3390/ijms22020863 - 16 Jan 2021

Cited by 4 | Viewed by 2668

Abstract

The Kv11.1 voltage-gated potassium channel, encoded by the KCNH2 gene, conducts the rapidly activating delayed rectifier current in the heart. KCNH2 pre-mRNA undergoes alternative polyadenylation to generate two C-terminal Kv11.1 isoforms in the heart. Utilization of a poly(A) signal in exon 15 produces [...] Read more.

The Kv11.1 voltage-gated potassium channel, encoded by the KCNH2 gene, conducts the rapidly activating delayed rectifier current in the heart. KCNH2 pre-mRNA undergoes alternative polyadenylation to generate two C-terminal Kv11.1 isoforms in the heart. Utilization of a poly(A) signal in exon 15 produces the full-length, functional Kv11.1a isoform, while intron 9 polyadenylation generates the C-terminally truncated, nonfunctional Kv11.1a-USO isoform. The relative expression of Kv11.1a and Kv11.1a-USO isoforms plays an important role in the regulation of Kv11.1 channel function. In this study, we tested the hypothesis that the RNA polyadenylate binding protein nuclear 1 (PABPN1) interacts with a unique 22 nt adenosine stretch adjacent to the intron 9 poly(A) signal and regulates KCNH2 pre-mRNA alternative polyadenylation and the relative expression of Kv11.1a C-terminal isoforms. We showed that PABPN1 inhibited intron 9 poly(A) activity using luciferase reporter assays, tandem poly(A) reporter assays, and RNA pulldown assays. We also showed that PABPN1 increased the relative expression level of the functional Kv11.1a isoform using RNase protection assays, immunoblot analyses, and patch clamp recordings. Our present findings suggest a novel role for the RNA-binding protein PABPN1 in the regulation of functional and nonfunctional Kv11.1 isoform expression. Full article

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

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Review

Jump to: Research

20 pages, 1705 KiB

Open AccessReview

Mutation-Specific Differences in Kv7.1 (KCNQ1) and Kv11.1 (KCNH2) Channel Dysfunction and Long QT Syndrome Phenotypes

by Peter M. Kekenes-Huskey, Don E. Burgess, Bin Sun, Daniel C. Bartos, Ezekiel R. Rozmus, Corey L. Anderson, Craig T. January, Lee L. Eckhardt and Brian P. Delisle

Int. J. Mol. Sci. 2022, 23(13), 7389; https://doi.org/10.3390/ijms23137389 - 2 Jul 2022

Cited by 7 | Viewed by 4095

Abstract

The electrocardiogram (ECG) empowered clinician scientists to measure the electrical activity of the heart noninvasively to identify arrhythmias and heart disease. Shortly after the standardization of the 12-lead ECG for the diagnosis of heart disease, several families with autosomal recessive (Jervell and Lange-Nielsen [...] Read more.

The electrocardiogram (ECG) empowered clinician scientists to measure the electrical activity of the heart noninvasively to identify arrhythmias and heart disease. Shortly after the standardization of the 12-lead ECG for the diagnosis of heart disease, several families with autosomal recessive (Jervell and Lange-Nielsen Syndrome) and dominant (Romano–Ward Syndrome) forms of long QT syndrome (LQTS) were identified. An abnormally long heart rate-corrected QT-interval was established as a biomarker for the risk of sudden cardiac death. Since then, the International LQTS Registry was established; a phenotypic scoring system to identify LQTS patients was developed; the major genes that associate with typical forms of LQTS were identified; and guidelines for the successful management of patients advanced. In this review, we discuss the molecular and cellular mechanisms for LQTS associated with missense variants in KCNQ1 (LQT1) and KCNH2 (LQT2). We move beyond the “benign” to a “pathogenic” binary classification scheme for different KCNQ1 and KCNH2 missense variants and discuss gene- and mutation-specific differences in K⁺ channel dysfunction, which can predispose people to distinct clinical phenotypes (e.g., concealed, pleiotropic, severe, etc.). We conclude by discussing the emerging computational structural modeling strategies that will distinguish between dysfunctional subtypes of KCNQ1 and KCNH2 variants, with the goal of realizing a layered precision medicine approach focused on individuals. Full article

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

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22 pages, 3068 KiB

Open AccessReview

Mechanisms and Regulation of Cardiac Ca_V1.2 Trafficking

by Maartje Westhoff and Rose E. Dixon

Int. J. Mol. Sci. 2021, 22(11), 5927; https://doi.org/10.3390/ijms22115927 - 31 May 2021

Cited by 11 | Viewed by 4397

Abstract

During cardiac excitation contraction coupling, the arrival of an action potential at the ventricular myocardium triggers voltage-dependent L-type Ca²⁺ (Ca_V1.2) channels in individual myocytes to open briefly. The level of this Ca²⁺ influx tunes the amplitude of Ca²⁺ [...] Read more.

During cardiac excitation contraction coupling, the arrival of an action potential at the ventricular myocardium triggers voltage-dependent L-type Ca²⁺ (Ca_V1.2) channels in individual myocytes to open briefly. The level of this Ca²⁺ influx tunes the amplitude of Ca²⁺-induced Ca²⁺ release from ryanodine receptors (RyR2) on the junctional sarcoplasmic reticulum and thus the magnitude of the elevation in intracellular Ca²⁺ concentration and ultimately the downstream contraction. The number and activity of functional Ca_V1.2 channels at the t-tubule dyads dictates the amplitude of the Ca²⁺ influx. Trafficking of these channels and their auxiliary subunits to the cell surface is thus tightly controlled and regulated to ensure adequate sarcolemmal expression to sustain this critical process. To that end, recent discoveries have revealed the existence of internal reservoirs of preformed Ca_V1.2 channels that can be rapidly mobilized to enhance sarcolemmal expression in times of acute stress when hemodynamic and metabolic demand increases. In this review, we provide an overview of the current thinking on Ca_V1.2 channel trafficking dynamics in the heart. We highlight the numerous points of control including the biosynthetic pathway, the endosomal recycling pathway, ubiquitination, and lysosomal and proteasomal degradation pathways, and discuss the effects of β-adrenergic and angiotensin receptor signaling cascades on this process. Full article

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

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15 pages, 641 KiB

Open AccessReview

Neurological Disorders and Risk of Arrhythmia

by Joyce Bernardi, Kelly A. Aromolaran and Ademuyiwa S. Aromolaran

Int. J. Mol. Sci. 2021, 22(1), 188; https://doi.org/10.3390/ijms22010188 - 27 Dec 2020

Cited by 24 | Viewed by 8987

Abstract

Neurological disorders including depression, anxiety, post-traumatic stress disorder (PTSD), schizophrenia, autism and epilepsy are associated with an increased incidence of cardiovascular disorders and susceptibility to heart failure. The underlying molecular mechanisms that link neurological disorders and adverse cardiac function are poorly understood. Further, [...] Read more.

Neurological disorders including depression, anxiety, post-traumatic stress disorder (PTSD), schizophrenia, autism and epilepsy are associated with an increased incidence of cardiovascular disorders and susceptibility to heart failure. The underlying molecular mechanisms that link neurological disorders and adverse cardiac function are poorly understood. Further, a lack of progress is likely due to a paucity of studies that investigate the relationship between neurological disorders and cardiac electrical activity in health and disease. Therefore, there is an important need to understand the spatiotemporal behavior of neurocardiac mechanisms. This can be advanced through the identification and validation of neurological and cardiac signaling pathways that may be adversely regulated. In this review we highlight how dysfunction of the hypothalamic–pituitary–adrenal (HPA) axis, autonomic nervous system (ANS) activity and inflammation, predispose to psychiatric disorders and cardiac dysfunction. Moreover, antipsychotic and antidepressant medications increase the risk for adverse cardiac events, mostly through the block of the human ether-a-go-go-related gene (hERG), which plays a critical role in cardiac repolarization. Therefore, understanding how neurological disorders lead to adverse cardiac ion channel remodeling is likely to have significant implications for the development of effective therapeutic interventions and helps improve the rational development of targeted therapeutics with significant clinical implications. Full article

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

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23 pages, 1963 KiB

Open AccessReview

Insights into Cardiac IKs (KCNQ1/KCNE1) Channels Regulation

by Xiaoan Wu and H. Peter Larsson

Int. J. Mol. Sci. 2020, 21(24), 9440; https://doi.org/10.3390/ijms21249440 - 11 Dec 2020

Cited by 25 | Viewed by 7753

Abstract

The delayed rectifier potassium IKs channel is an important regulator of the duration of the ventricular action potential. Hundreds of mutations in the genes (KCNQ1 and KCNE1) encoding the IKs channel cause long QT syndrome (LQTS). LQTS is a heart disorder [...] Read more.

The delayed rectifier potassium IKs channel is an important regulator of the duration of the ventricular action potential. Hundreds of mutations in the genes (KCNQ1 and KCNE1) encoding the IKs channel cause long QT syndrome (LQTS). LQTS is a heart disorder that can lead to severe cardiac arrhythmias and sudden cardiac death. A better understanding of the IKs channel (here called the KCNQ1/KCNE1 channel) properties and activities is of great importance to find the causes of LQTS and thus potentially treat LQTS. The KCNQ1/KCNE1 channel belongs to the superfamily of voltage-gated potassium channels. The KCNQ1/KCNE1 channel consists of both the pore-forming subunit KCNQ1 and the modulatory subunit KCNE1. KCNE1 regulates the function of the KCNQ1 channel in several ways. This review aims to describe the current structural and functional knowledge about the cardiac KCNQ1/KCNE1 channel. In addition, we focus on the modulation of the KCNQ1/KCNE1 channel and its potential as a target therapeutic of LQTS. Full article

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

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13 pages, 915 KiB

Open AccessReview

Towards the Development of AgoKirs: New Pharmacological Activators to Study K_ir2.x Channel and Target Cardiac Disease

by Laura van der Schoor, Emma J. van Hattum, Sophie M. de Wilde, Netanja I. Harlianto, Aart-Jan van Weert, Meye Bloothooft and Marcel A. G. van der Heyden

Int. J. Mol. Sci. 2020, 21(16), 5746; https://doi.org/10.3390/ijms21165746 - 11 Aug 2020

Cited by 6 | Viewed by 3272

Abstract

Inward rectifier potassium ion channels (I_K1-channels) of the K_ir2.x family are responsible for maintaining a stable negative resting membrane potential in excitable cells, but also play a role in processes of non-excitable tissues, such as bone development. I_K1 [...] Read more.

Inward rectifier potassium ion channels (I_K1-channels) of the K_ir2.x family are responsible for maintaining a stable negative resting membrane potential in excitable cells, but also play a role in processes of non-excitable tissues, such as bone development. I_K1-channel loss-of-function, either congenital or acquired, has been associated with cardiac disease. Currently, basic research and specific treatment are hindered by the absence of specific and efficient K_ir2.x channel activators. However, twelve different compounds, including approved drugs, show off-target I_K1 activation. Therefore, these compounds contain valuable information towards the development of agonists of K_ir channels, AgoKirs. We reviewed the mechanism of I_K1 channel activation of these compounds, which can be classified as direct or indirect activators. Subsequently, we examined the most viable starting points for rationalized drug development and possible safety concerns with emphasis on cardiac and skeletal muscle adverse effects of AgoKirs. Finally, the potential value of AgoKirs is discussed in view of the current clinical applications of potentiators and activators in cystic fibrosis therapy. Full article

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

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