Molecular Physiology of Cardiac Repolarization

2005 ◽  
Vol 85 (4) ◽  
pp. 1205-1253 ◽  
Author(s):  
Jeanne M. Nerbonne ◽  
Robert S. Kass
Keyword(s):  
Ion Channels ◽  
Action Potential ◽  
Action Potentials ◽  
Molecular Mechanisms ◽  
Protein Complexes ◽  
Future Research ◽  
Cardiac Repolarization ◽  
Molecular Physiology ◽  
Cardiac Ion Channels ◽  
Α Subunits

The heart is a rhythmic electromechanical pump, the functioning of which depends on action potential generation and propagation, followed by relaxation and a period of refractoriness until the next impulse is generated. Myocardial action potentials reflect the sequential activation and inactivation of inward (Na+ and Ca2+) and outward (K+) current carrying ion channels. In different regions of the heart, action potential waveforms are distinct, owing to differences in Na+, Ca2+, and K+ channel expression, and these differences contribute to the normal, unidirectional propagation of activity and to the generation of normal cardiac rhythms. Changes in channel functioning, resulting from inherited or acquired disease, affect action potential repolarization and can lead to the generation of life-threatening arrhythmias. There is, therefore, considerable interest in understanding the mechanisms that control cardiac repolarization and rhythm generation. Electrophysiological studies have detailed the properties of the Na+, Ca2+, and K+ currents that generate cardiac action potentials, and molecular cloning has revealed a large number of pore forming (α) and accessory (β, δ, and γ) subunits thought to contribute to the formation of these channels. Considerable progress has been made in defining the functional roles of the various channels and in identifying the α-subunits encoding these channels. Much less is known, however, about the functioning of channel accessory subunits and/or posttranslational processing of the channel proteins. It has also become clear that cardiac ion channels function as components of macromolecular complexes, comprising the α-subunits, one or more accessory subunit, and a variety of other regulatory proteins. In addition, these macromolecular channel protein complexes appear to interact with the actin cytoskeleton and/or the extracellular matrix, suggesting important functional links between channel complexes, as well as between cardiac structure and electrical functioning. Important areas of future research will be the identification of (all of) the molecular components of functional cardiac ion channels and delineation of the molecular mechanisms involved in regulating the expression and the functioning of these channels in the normal and the diseased myocardium.

scholarly journals Individual Contributions of Cardiac Ion Channels on Atrial Repolarization and Reentrant Waves: A Multiscale In-Silico Study

2022 ◽  
Vol 9 (1) ◽  
pp. 28
Author(s):  
Henry Sutanto
Keyword(s):  
Ion Channels ◽  
Action Potential ◽  
In Silico ◽  
Computational Study ◽  
Surrogate Marker ◽  
Cardiac Ion Channels ◽  
Atrial Electrophysiology ◽  
In Silico Study ◽  
In Silico Models ◽  
Atrial Repolarization

The excitation, contraction, and relaxation of an atrial cardiomyocyte are maintained by the activation and inactivation of numerous cardiac ion channels. Their collaborative efforts cause time-dependent changes of membrane potential, generating an action potential (AP), which is a surrogate marker of atrial arrhythmias. Recently, computational models of atrial electrophysiology emerged as a modality to investigate arrhythmia mechanisms and to predict the outcome of antiarrhythmic therapies. However, the individual contribution of atrial ion channels on atrial action potential and reentrant arrhythmia is not yet fully understood. Thus, in this multiscale in-silico study, perturbations of individual atrial ionic currents (INa, Ito, ICaL, IKur, IKr, IKs, IK1, INCX and INaK) in two in-silico models of human atrial cardiomyocyte (i.e., Courtemanche-1998 and Grandi-2011) were performed at both cellular and tissue levels. The results show that the inhibition of ICaL and INCX resulted in AP shortening, while the inhibition of IKur, IKr, IKs, IK1 and INaK prolonged AP duration (APD). Particularly, in-silico perturbations (inhibition and upregulation) of IKr and IKs only minorly affected atrial repolarization in the Grandi model. In contrast, in the Courtemanche model, the inhibition of IKr and IKs significantly prolonged APD and vice versa. Additionally, a 50% reduction of Ito density abbreviated APD in the Courtemanche model, while the same perturbation prolonged APD in the Grandi model. Similarly, a strong model dependence was also observed at tissue scale, with an observable IK1-mediated reentry stabilizing effect in the Courtemanche model but not in the Grandi atrial model. Moreover, the Grandi model was highly sensitive to a change on intracellular Ca2+ concentration, promoting a repolarization failure in ICaL upregulation above 150% and facilitating reentrant spiral waves stabilization by ICaL inhibition. Finally, by incorporating the previously published atrial fibrillation (AF)-associated ionic remodeling in the Courtemanche atrial model, in-silico modeling revealed the antiarrhythmic effect of IKr inhibition in both acute and chronic settings. Overall, our multiscale computational study highlights the strong model-dependent effects of ionic perturbations which could affect the model’s accuracy, interpretability, and prediction. This observation also suggests the need for a careful selection of in-silico models of atrial electrophysiology to achieve specific research aims.

Abstract 63: Potential Genetic and Pharmacological Protection from Virus-induced Ventricular Arrhythmias and Sudden Cardiac Death

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Nathalie Strutz-eebohm ◽  
Katja Steinke ◽  
Ulrike Henrion ◽  
Matthias Rohbeck ◽  
Karin Klingel ◽  
...  
Keyword(s):  
Ion Channels ◽  
Sudden Cardiac Death ◽  
Action Potentials ◽  
Cardiac Death ◽  
Ventricular Arrhythmias ◽  
Proper Function ◽  
Channel Trafficking ◽  
Cardiac Ion Channels ◽  
Evolutionary Advantage ◽  
Group B

In patients as well as in mouse models, enteroviral infections, especially Coxsackie group B viruses (CVB1-6), frequently induce ventricular arrhythmias and sudden cardiac death. The cardiac action potential requires proper function of cardiac ion channels. CVB3 alters Kv7.1 channel trafficking potentially leading to changes in action potentials and increasing likelihood of arrhythmias. Genetic variants of cardiac ion channels can cause changes in channel trafficking that may preserve from CVB3 modulations and present an evolutionary advantage. Here, we show that a common polymorphic Kv7.1 channel variant uses alternative trafficking pathways and may thus exert a benefit during CVB3 infections. Genetic and pharmacological disruption of a CVB3-stimulated Serum- and Glucocorticoid inducible Kinase 1 (SGK1) pathways blunts Kv7.1 channel dysfunctions. Our results suggest that escape from CVB3-induced SGK1-stimulation by genetic variation in Kv7.1 may be protective and inhibition of SGK1 may present a pharmacological approach to reduce the pro-arrhythmic risk associated with acute coxsackievirus infections.

scholarly journals Dendritic Voltage-Gated Ion Channels Regulate the Action Potential Firing Mode of Hippocampal CA1 Pyramidal Neurons

1999 ◽  
Vol 82 (4) ◽  
pp. 1895-1901 ◽  
Author(s):  
Jeffrey C. Magee ◽  
Michael Carruth
Keyword(s):  
Ion Channels ◽  
Action Potential ◽  
Large Amplitude ◽  
Action Potentials ◽  
Pyramidal Neurons ◽  
Burst Firing ◽  
Voltage Gated ◽  
Ca1 Pyramidal Neurons ◽  
Firing Mode ◽  
Voltage Gated Ion Channels

The role of dendritic voltage-gated ion channels in the generation of action potential bursting was investigated using whole cell patch-clamp recordings from the soma and dendrites of CA1 pyramidal neurons located in hippocampal slices of adult rats. Under control conditions somatic current injections evoked single action potentials that were associated with an afterhyperpolarization (AHP). After localized application of 4-aminopyridine (4-AP) to the distal apical dendritic arborization, the same current injections resulted in the generation of an afterdepolarization (ADP) and multiple action potentials. This burst firing was not observed after localized application of 4-AP to the soma/proximal dendrites. The dendritic 4-AP application allowed large-amplitude Na+-dependent action potentials, which were prolonged in duration, to backpropagate into the distal apical dendrites. No change in action potential backpropagation was seen with proximal 4-AP application. Both the ADP and action potential bursting could be inhibited by the bath application of nonspecific concentrations of divalent Ca2+ channel blockers (NiCl and CdCl). Ca2+ channel blockade also reduced the dendritic action potential duration without significantly affecting spike amplitude. Low concentrations of TTX (10–50 nM) also reduced the ability of the CA1 neurons to fire in the busting mode. This effect was found to be the result of an inhibition of backpropagating dendritic action potentials and could be overcome through the coordinated injection of transient, large-amplitude depolarizing current into the dendrite. Dendritic current injections were able to restore the burst firing mode (represented as a large ADP) even in the presence of high concentrations of TTX (300–500 μM). These data suggest the role of dendritic Na+ channels in bursting is to allow somatic/axonal action potentials to backpropagate into the dendrites where they then activate dendritic Ca2+ channels. Although it appears that most Ca2+ channel subtypes are important in burst generation, blockade of T- and R-type Ca2+ channels by NiCl (75 μM) inhibited action potential bursting to a greater extent than L-channel (10 μM nimodipine) or N-, P/Q-type (1 μM ω-conotoxin MVIIC) Ca2+ channel blockade. This suggest that the Ni-sensitive voltage-gated Ca2+ channels have the most important role in action potential burst generation. In summary, these data suggest that the activation of dendritic voltage-gated Ca2+ channels, by large-amplitude backpropagating spikes, provides a prolonged inward current that is capable of generating an ADP and burst of multiple action potentials in the soma of CA1 pyramidal neurons. Dendritic voltage-gated ion channels profoundly regulate the processing and storage of incoming information in CA1 pyramidal neurons by modulating the action potential firing mode from single spiking to burst firing.

Abstract MP110: Inhibition of the Unfolded Protein Response Reduces Arrhythmic Risk After Myocardial Infarction

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Man Liu ◽  
Hong Liu ◽  
Preethy Parthiban ◽  
guangbin shi ◽  
Gyeoung-Jin Kang ◽  
...  
Keyword(s):  
Ion Channels ◽  
Action Potential ◽  
Ion Channel ◽  
Unfolded Protein Response ◽  
Coronary Artery Ligation ◽  
Unfolded Protein ◽  
Cardiac Ion Channels ◽  
Increased Risk ◽  
The Unfolded Protein Response ◽  
Protein Response

Background: Ischemic cardiomyopathy is associated with an increased risk of sudden death, activation of the unfolded protein response (UPR), and reductions in multiple cardiac ion channels and transporters. When activated, the protein kinase-like ER kinase (PERK) arm of the unfolded protein response (UPR) reduces protein translation and abundance. We hypothesize that inhibition of PERK could prevent cardiac ion channel downregulation and reduce arrhythmic risk after myocardial infarct (MI). Methods: The MI mouse model was induced by a left anterior descending coronary artery ligation. Pharmacological inhibition of PERK was achieved with a specific inhibitor, GSK2606414. Genetic inhibition of PERK was achieved by cardiac-specific PERK knockout in C57BL/6J mice (PERKKO). Echocardiography, telemetry, and electrophysiological measurements were performed to monitor cardiac function and arrhythmias. Results: Three weeks after surgery, the wild type MI mice exhibited decreased ejection fraction (EF%), ventricular tachycardia (VT) and prolonged QTc intervals. The UPR effectors (phospho-PERK, phospho-IRE1, and ATF6N) were elevated significantly (1.7- to 5.9-fold) at protein levels, and all major cardiac ion channels showed decreased protein expression in MI hearts. MI cardiomyocytes showed decreased currents for all major channels (I Na , I CaL , I to , I K1 , and I Kur : 60±6%, 53±9%, 27±6%, 55±7%, and 40±7% of sham, respectively, P<0.05 vs. sham) with significantly prolonged action potential duration (APD 90 : 291±43 ms of MI vs. 100±12 ms of sham, P<0.05) and decreased maximum upstroke velocity (dV/dt max : 95±4 V/s of MI vs. 132±6 ms of sham, P<0.05) of the action potential phase 0. GSK treatment restored I Na and I to , shortened APD, and increased dV/dt max . PERKKO mice exhibited reduced electrical remodeling in response to MI with shortened QTc intervals, less VT episodes, and higher survival rates. Conclusion: PERK is activated during MI and contributes to arrhythmic risk by downregulation of select cardiac ion channels. PERK inhibition prevented these changes and reduced arrhythmic risk. These results suggest that ion channel downregulation during MI is a fundamental arrhythmic mechanism and maintaining ion channel levels is antiarrhythmic.

Transmural action potential and ionic current remodeling in ventricles of failing canine hearts

2002 ◽  
Vol 283 (3) ◽  
pp. H1031-H1041 ◽  
Author(s):  
Gui-Rong Li ◽  
Chu-Pak Lau ◽  
Anique Ducharme ◽  
Jean-Claude Tardif ◽  
Stanley Nattel
Keyword(s):  
Left Ventricle ◽  
Action Potential ◽  
Action Potentials ◽  
Slow Component ◽  
Ionic Current ◽  
Ionic Currents ◽  
Cell Types ◽  
Delayed Rectifier ◽  
Cardiac Repolarization ◽  
Early Afterdepolarizations

Heart failure (HF) produces important alterations in currents underlying cardiac repolarization, but the transmural distribution of such changes is unknown. We therefore recorded action potentials and ionic currents in cells isolated from the endocardium, midmyocardium, and epicardium of the left ventricle from dogs with and without tachypacing-induced HF. HF greatly increased action potential duration (APD) but attenuated APD heterogeneity in the three regions. Early afterdepolarizations (EADs) were observed in all cell types of failing hearts but not in controls. Inward rectifier K+ current ( I K1) was homogeneously reduced by ∼41% (at −60 mV) in the three cell types. Transient outward K+ current ( I to1) was decreased by 43–45% at +30 mV, and the slow component of the delayed rectifier K+ current ( I Ks) was significantly downregulated by 57%, 49%, and 58%, respectively, in epicardial, midmyocardial, and endocardial cells, whereas the rapid component of the delayed rectifier K+ current was not altered. The results indicate that HF remodels electrophysiology in all layers of the left ventricle, and the downregulation of I K1, I to1, and I Ks increases APD and favors occurrence of EADs.

scholarly journals Ion Channels in Endothelial Responses to Fluid Shear Stress

Physiology ◽  
2016 ◽  
Vol 31 (5) ◽  
pp. 359-369 ◽  
Author(s):  
Kristin A. Gerhold ◽  
Martin A. Schwartz
Keyword(s):  
Shear Stress ◽  
Ion Channels ◽  
Molecular Mechanisms ◽  
Fluid Shear Stress ◽  
Future Research ◽  
Fluid Shear ◽  
Environmental Cue ◽  
Vascular Physiology

Fluid shear stress is an important environmental cue that governs vascular physiology and pathology, but the molecular mechanisms that mediate endothelial responses to flow are only partially understood. Gating of ion channels by flow is one mechanism that may underlie many of the known responses. Here, we review the literature on endothelial ion channels whose activity is modulated by flow with an eye toward identifying important questions for future research.

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