scholarly journals Inhibition of Histone Deacetylases Induces K+ Channel Remodeling and Action Potential Prolongation in HL-1 Atrial Cardiomyocytes

2018 ◽  
Vol 49 (1) ◽  
pp. 65-77 ◽  
Author(s):  
Patrick Lugenbiel ◽  
Katharina Govorov ◽  
Ann-Kathrin Rahm ◽  
Teresa Wieder ◽  
Dominik Gramlich ◽  
...  
Keyword(s):  
Action Potential ◽  
Ion Channel ◽  
Action Potential Duration ◽  
Histone Deacetylases ◽  
Trichostatin A ◽  
Class I ◽  
K Channel ◽  
Hdac Inhibition ◽  
Atrial Cardiomyocytes ◽  
Channel Expression

Background/Aims: Cardiac arrhythmias are triggered by environmental stimuli that may modulate expression of cardiac ion channels. Underlying epigenetic regulation of cardiac electrophysiology remains incompletely understood. Histone deacetylases (HDACs) control gene expression and cardiac integrity. We hypothesized that class I/II HDACs transcriptionally regulate ion channel expression and determine action potential duration (APD) in cardiac myocytes. Methods: Global class I/II HDAC inhibition was achieved by administration of trichostatin A (TSA). HDAC-mediated effects on K+ channel expression and electrophysiological function were evaluated in murine atrial cardiomyocytes (HL-1 cells) using real-time PCR, Western blot, and patch clamp analyses. Electrical tachypacing was employed to recapitulate arrhythmia-related effects on ion channel remodeling in the absence and presence of HDAC inhibition. Results: Global HDAC inhibition increased histone acetylation and prolonged APD90 in atrial cardiomyocytes compared to untreated control cells. Transcript levels of voltage-gated or inwardly rectifying K+ channels Kcnq1, Kcnj3 and Kcnj5 were significantly reduced, whereas Kcnk2, Kcnj2 and Kcnd3 mRNAs were upregulated. Ion channel remodeling was similarly observed at protein level. Short-term tachypacing did not induce significant transcriptional K+ channel remodeling. Conclusion: The present findings link class I/II HDAC activity to regulation of ion channel expression and action potential duration in atrial cardiomyocytes. Clinical implications for HDAC-based antiarrhythmic therapy and cardiac safety of HDAC inhibitors require further investigation.

scholarly journals Ion Channel and Structural Remodeling in Obesity-Mediated Atrial Fibrillation

2020 ◽  
Vol 13 (8) ◽  
Author(s):  
Mark D. McCauley ◽  
Liang Hong ◽  
Arvind Sridhar ◽  
Ambili Menon ◽  
Srikanth Perike ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Action Potential ◽  
Ion Channel ◽  
Sodium Channel ◽  
Action Potential Duration ◽  
Obese Mice ◽  
Atrial Fibrosis ◽  
Structural Remodeling ◽  
Cardiac Sodium Channel ◽  
Channel Expression

Background: Epidemiological studies have established obesity as an independent risk factor for atrial fibrillation (AF), but the underlying pathophysiological mechanisms remain unclear. Reduced cardiac sodium channel expression is a known causal mechanism in AF. We hypothesized that obesity decreases Nav1.5 expression via enhanced oxidative stress, thus reducing I Na , and enhancing susceptibility to AF. Methods: To elucidate the underlying electrophysiological mechanisms a diet-induced obese mouse model was used. Weight, blood pressure, glucose, F 2 -isoprostanes, NOX2 (NADPH oxidase 2), and PKC (protein kinase C) were measured in obese mice and compared with lean controls. Invasive electrophysiological, immunohistochemistry, Western blotting, and patch clamping of membrane potentials was performed to evaluate the molecular and electrophysiological phenotype of atrial myocytes. Results: Pacing-induced AF in 100% of diet-induced obese mice versus 25% in controls ( P <0.01) with increased AF burden. Cardiac sodium channel expression, I Na and atrial action potential duration were reduced and potassium channel expression (Kv1.5) and current ( I Kur ) and F 2 -isoprostanes, NOX2, and PKC-α/δ expression and atrial fibrosis were significantly increased in diet-induced obese mice as compared with controls. A mitochondrial antioxidant reduced AF burden, restored I Na , I Ca,L , I Kur , action potential duration, and reversed atrial fibrosis in diet-induced obese mice as compared with controls. Conclusions: Inducible AF in obese mice is mediated, in part, by a combined effect of sodium, potassium, and calcium channel remodeling and atrial fibrosis. Mitochondrial antioxidant therapy abrogated the ion channel and structural remodeling and reversed the obesity-induced AF burden. Our findings have important implications for the management of obesity-mediated AF in patients. Graphic Abstract: A graphic abstract is available for this article.

scholarly journals Ion channel expression and electrophysiology of singular human (primary and induced pluripotent stem cell derived) cardiomyocytes

2021 ◽  
Author(s):  
Christina Schmid ◽  
Najah Abi-Gerges ◽  
Dietmar Zellner ◽  
Georg Rast
Keyword(s):  
Ion Channels ◽  
Action Potential ◽  
Ion Channel ◽  
Single Cell ◽  
Action Potential Duration ◽  
Drug Effects ◽  
Induced Pluripotent Stem Cell ◽  
Inward Current ◽  
Beat Rate ◽  
Channel Expression

SUMMARYHuman induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and primary human cardiomyocytes are used for in vitro cardiac safety testing. hiPSC-CMs have been associated with a vast heterogeneity regarding single-cell morphology, beating behavior and action potential duration, prompting a systematic analysis of single-cell characteristics. Previously published hiPSC-CM studies revealed action potentials with nodal-, atrial- or ventricular-like morphology, although ion channel expression of singular hiPSC-CMs is not fully understood. Other studies used single-cell RNA-sequencing, however, these studies did not extensively focus on expression patterns of cardiac ion channels or failed to detect ion channel transcripts. Thus, the current study used a single-cell patch-clamp-RT-qPCR approach to get insights into single-cell electrophysiology (capacitance, action potential duration at 90% of repolarization, upstroke velocity, spontaneous beat rate, and sodium-driven fast inward current) and ion channel expression (HCN4, CACNA1G, CACNA1D, KCNA5, KCNJ4, SCN5A, KCNJ2, CACNA1D, and KCNH2), the combination of both within individual cells, and their correlations in single cardiomyocytes. We used commercially available hiPSC-CMs (iCell cardiomyocytes, atrial and ventricular Pluricytes) and primary human adult atrial and ventricular cardiomyocytes. Recordings of electrophysiological parameters revealed differences between the cell groups and variation within the hiPSC-CMs groups as well as within primary ventricular cardiomyocytes. Expression analysis on mRNA level showed no-clear-cut discrimination between primary cardiac subtypes and revealed both similarities and differences between all cell groups. Higher expression of atrial-associated ion channels in primary atrial cardiomyocytes and atrial Pluricytes compared to their ventricular counterpart indicates a successful chamber-specific hiPSC differentiation. Interpretation of correlations between the single-cell parameters was challenging, as the total data set is complex, particularly for parameters depending on multiple processes, like the spontaneous beat rate. Yet, for example, expression of SCN5A correlated well with the fast inward current amplitude for all three hiPSC-CM groups. To further enhance our understanding of the physiology and composition of the investigated hiPSC-CMs, we compared beating and non-beating cells and assessed distributions of single-cell data. Investigating the single-cell phenotypes of hiPSC-CMs revealed a combination of attributes which may be interpreted as a mixture of traits of different adult cardiac cell types: (i) nodal-related pacemaking attributes are spontaneous generation of action potentials and high HCN4 expression; and (ii) non-nodal attributes: cells have a prominent INa-driven fast inward current, a fast upstroke velocity and a high expression of SCN5A. In conclusion, the combination of nodal- and non-nodal attributes in single hiPSC-CMs may hamper the interpretation of drug effects on complex electrophysiological parameters like beat rate and action potential duration. However, the proven expression of specific ion channels enables the evaluation of drug effects on ionic currents in a more realistic environment than in recombinant systems.

scholarly journals Synapse-Level Determination of Action Potential Duration by K + Channel Clustering in Axons

Neuron ◽  
2016 ◽  
Vol 91 (2) ◽  
pp. 370-383 ◽  
Author(s):  
Matthew J.M. Rowan ◽  
Gina DelCanto ◽  
Jianqing J. Yu ◽  
Naomi Kamasawa ◽  
Jason M. Christie
Keyword(s):  
Action Potential ◽  
Action Potential Duration ◽  
K Channel

scholarly journals Differential regulation of K Ca 2.1 ( KCNN1 ) K + channel expression by histone deacetylases in atrial fibrillation with concomitant heart failure

2021 ◽  
Vol 9 (11) ◽  
Author(s):  
Ann‐Kathrin Rahm ◽  
Teresa Wieder ◽  
Dominik Gramlich ◽  
Mara Elena Müller ◽  
Maximilian N. Wunsch ◽  
...  
Keyword(s):  
Heart Failure ◽  
Atrial Fibrillation ◽  
Histone Deacetylases ◽  
Differential Regulation ◽  
K Channel ◽  
Channel Expression

scholarly journals Electrophysiological Biomarkers for Age-Related Changes in Human Atrial Cardiomyocytes: In Silico Study

2020 ◽  
Vol 31 ◽  
pp. 01004 ◽  
Author(s):  
Tatyana Nesterova ◽  
Konstantin Ushenin ◽  
Dmitry Shmarko ◽  
Olga Solovyova
Keyword(s):  
Experimental Data ◽  
Action Potential ◽  
Action Potential Duration ◽  
Cellular Response ◽  
Experimental Studies ◽  
Model Parameters ◽  
Human Cardiomyocytes ◽  
Atrial Cardiomyocytes ◽  
Age Related ◽  
Age Related Changes

Age-related changes in human cardiomyocytes are closely related to cardiac diseases, especially atrial fibrillation. Restricted availability of biological preparations from the human atrial myocardium complicates experimental studies on the aging processes in cardiomyocytes. In this preliminary study, we used available experimental data on the age-related changes in ionic conductances in canine atrial cardiomyocytes to predict possible consequences of similar remodeling in humans using two mathematical models (Courtemanche98 and Maleckar09) of human atrial cardiomyocytes. The study was performed using the model population approach, allowing one to assess variability in the cellular response to different interventions affecting model parameters. Here, this approach was used to evaluate the effects of age-related parameter modulation on action potential biomarkers in the two models. Simulation results show a significant decrease in the action potential duration and membrane potential at 20% of the action potential duration in aging. These model predictions are consistent with experimental data from mammalians. The action potential characteristics are shown to serve as notable biomarkers of age-related electrophysiological remodeling in human atrial cardiomyocytes. A comparison of the two models shows different behavior in the prediction of repolarization abnormalities.

scholarly journals Inhibition of Ca2+-activated large-conductance K+ channel activity alters synaptic AMPA receptor phenotype in mouse cerebellar stellate cells

2011 ◽  
Vol 106 (1) ◽  
pp. 144-152 ◽  
Author(s):  
Yu Liu ◽  
Iaroslav Savtchouk ◽  
Shoana Acharjee ◽  
Siqiong June Liu
Keyword(s):  
Potassium Channels ◽  
Action Potential ◽  
Action Potential Duration ◽  
Action Potentials ◽  
Channel Blocker ◽  
Stellate Cells ◽  
Bk Channels ◽  
Bk Channel ◽  
K Channel ◽  
Duration Of Action

Many fast-spiking inhibitory interneurons, including cerebellar stellate cells, fire brief action potentials and express α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-type glutamate receptors (AMPAR) that are permeable to Ca2+ and do not contain the GluR2 subunit. In a recent study, we found that increasing action potential duration promotes GluR2 gene transcription in stellate cells. We have now tested the prediction that activation of potassium channels that control the duration of action potentials can suppress the expression of GluR2-containing AMPARs at stellate cell synapses. We find that large-conductance Ca2+-activated potassium (BK) channels mediate a large proportion of the depolarization-evoked noninactivating potassium current in stellate cells. Pharmacological blockade of BK channels prolonged the action potential duration in postsynaptic stellate cells and altered synaptic AMPAR subtype from GluR2-lacking to GluR2-containing Ca2+-impermeable AMPARs. An L-type channel blocker abolished an increase in Ca2+ entry that was associated with spike broadening and also prevented the BK channel blocker-induced switch in AMPAR phenotype. Thus blocking BK potassium channels prolongs the action potential duration and increases the expression of GluR2-containing receptors at the synapse by enhancing Ca2+ entry in cerebellar stellate cells.

Termination of Action Potential Due to Site Selective Ion Channel Blockers

2019 ◽  
Vol 19 (02) ◽  
pp. 2050015
Author(s):  
Krishnendu Pal ◽  
Gautam Gangopadhyay
Keyword(s):  
Action Potential ◽  
Ion Channel ◽  
Sodium Channel ◽  
Action Potential Duration ◽  
Ionic Current ◽  
Channel Blockers ◽  
Quiescent State ◽  
Ion Channel Blockers ◽  
Different Types ◽  
Site Selective

Here, we have provided a qualitative theoretical description about how the action potential generation and its associated intrinsic properties such as ionic current, spiking frequency, action potential duration, gating dynamics, etc. are affected due to site selective ion channel blockers, by suitably adapting Gillespie’s stochastic simulation technique to an extended Hodgkin–Huxley Markov model, representing a very basic type of neuron. Considering different types and degrees of blocking potency of channel blockers to channel proteins, we have found that the nature of action potential termination process and corresponding ionic current profiles are very distinct from each other. With the increasing blocking affinity, the frequency of action potential spiking falls off exponentially in presence of sodium channel only blockers and dual type blockers having more sodium binding potency than potassium blockers, whereas in contrast, for potassium channel only blockers, dual type blockers having equal or higher potassium blocking affinity with respect to sodium blocking, the spiking frequency initially is enhanced followed by a gradual decrease due to the competition between channel number fluctuation and overall sodium and potassium conductances. Sodium channel blockers tend to shorten the action potential duration while the potassium channel blockers broaden it. The channel gating dynamics are also found to be changed drastically for different types of blockers. The final quiescent state arrival time and the quiescent state membrane voltage profiles show distinct features for different types of channel blockers with different applied external stimulus. Finally, we showed how consistent our results are with the existing literature of experimentally observed channel blocking effects in diverse systems and compared the similarities, dissimilarities and advantages of our model with an existing theoretical drug binding model with Langevin description. Our approach provides a qualitative pathway to investigate the effects of many other types of blocking mechanisms such as closed state, inactivated state blocking with desired level of structural and functional details.

Restoring depressed HERG K+ channel function as a mechanism for insulin treatment of abnormal QT prolongation and associated arrhythmias in diabetic rabbits

2006 ◽  
Vol 291 (3) ◽  
pp. H1446-H1455 ◽  
Author(s):  
Yiqiang Zhang ◽  
Jiening Xiao ◽  
Huizhen Wang ◽  
Xiaobin Luo ◽  
Jingxiong Wang ◽  
...  
Keyword(s):  
Action Potential ◽  
Action Potential Duration ◽  
Rabbit Model ◽  
Clinical Problem ◽  
Qt Prolongation ◽  
Dependent Diabetes Mellitus ◽  
K Channel ◽  
Delayed Rectifier ◽  
Diabetic Patients ◽  
Qtc Interval

Abnormal QT prolongation (QT-P) in diabetic patients has become a nonnegligible clinical problem and has attracted increasing attention from basic scientists, because it increases the risk of lethal ventricular arrhythmias. Correction of QT-P may be an important measure in minimizing sudden cardiac death in diabetic patients. Here we report the efficacy of insulin in preventing QT-P and the associated arrhythmias and the mechanisms underlying the effects in a rabbit model of type 1 insulin-dependent diabetes mellitus (IDDM). The heart rate-corrected QT (QTc) interval and action potential duration were considerably prolonged, with frequent ventricular tachycardias. The rapid delayed rectifier K+ current ( IKr) was markedly reduced in IDDM hearts, and hyperglycemia depressed the function of the human ether-a-go-go-related gene (HERG), which conducts IKr. The impairment was primarily ascribed to the enhanced oxidative damage to the myocardium, as indicated by the increased intracellular level of reactive oxygen species and simultaneously decreased endogenous antioxidant reserve and by the increased lipid peroxidation and protein oxidation. Moreover, IDDM or hyperglycemia resulted in downregulation of HERG protein level. Insulin restored the depressed IKr/HERG and prevented QTc/action potential duration prolongation and the associated arrhythmias, and the beneficial actions of insulin are partially due to its antioxidant ability. Our study represents the first documentation of oxidative stress as the major metabolic mechanism for HERG K+ dysfunction, which causes diabetic QT-P, and suggests IKr/HERG as a potential therapeutic target for treatment of the disorder.

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