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 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 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.

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.

Block of hERG K+ channel and prolongation of action potential duration by fluphenazine at submicromolar concentration

2013 ◽  
Vol 702 (1-3) ◽  
pp. 165-173 ◽  
Author(s):  
Hee-Kyung Hong ◽  
Byung Hoon Lee ◽  
Mi-Hyeong Park ◽  
Seung Ho Lee ◽  
Daehyun Chu ◽  
...  
Keyword(s):  
Action Potential ◽  
Action Potential Duration ◽  
K Channel ◽  
Prolongation Of Action Potential

Mechanisms Underlying the QT Interval–prolonging Effects of Sevoflurane and Its Interactions with Other QT-prolonging Drugs

2006 ◽  
Vol 104 (5) ◽  
pp. 1015-1022 ◽  
Author(s):  
Jiesheng Kang ◽  
William P. Reynolds ◽  
Xiao-Liang Chen ◽  
Junzhi Ji ◽  
Hongge Wang ◽  
...  
Keyword(s):  
Action Potential ◽  
Action Potential Duration ◽  
Antiarrhythmic Drugs ◽  
Ventricular Repolarization ◽  
K Channel ◽  
Na Channel ◽  
Ca Channel ◽  
Class Iii ◽  
K Channels ◽  
Channel Currents

Background Sevoflurane prolongs ventricular repolarization in patients, but the mechanisms are not fully characterized. The effects of sevoflurane on many cloned human cardiac ion channels have not been studied, and the interactions between sevoflurane and other drugs that prolong cardiac repolarization have not been detailed. Methods The effects of sevoflurane on action potentials and L-type Ca channels in guinea pig myocytes were examined. Sevoflurane's effects on cloned human cardiac K channels and the cloned human cardiac Na channel were studied. The consequences of combining sevoflurane and the class III antiarrhythmic drugs sotalol or dofetilide on action potential duration were also examined. Results Sevoflurane produced an increase in action potential duration at concentrations of 0.3-1 mm. Contrary to most drugs that delay ventricular repolarization, sevoflurane was without effect on the human ether-a-go-go-related gene cardiac potassium channel but instead produced a reduction in KvLQT1/minK K channel currents and inhibited the Kv4.3 K channel by speeding its apparent rate of inactivation. Sevoflurane had little effect on Na and Ca channel currents at concentrations of 1 mm or less. When the authors coadministered sevoflurane with sotalol or dofetilide, synergistic effects on repolarization were observed, resulting in large increases in action potential duration (up to 66%). Conclusion Prolonged ventricular repolarization observed with administration of sevoflurane results from inhibition of KvLQT1/minK and Kv4.3 cardiac K channels. Combining sevoflurane with class III antiarrhythmic drugs results in supra-additive effects on action potential duration. The results indicate that sevoflurane, when administered with this class of drug, could result in excessive delays in ventricular repolarization. The results suggest the need for further clinical studies.

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