scholarly journals Genetic ablation or pharmacological inhibition of Kv1.1 potassium channel subunits impairs atrial repolarization in mice

2019 ◽  
Vol 316 (2) ◽  
pp. C154-C161 ◽  
Author(s):  
Man Si ◽  
Krystle Trosclair ◽  
Kathryn A. Hamilton ◽  
Edward Glasscock
Keyword(s):  
Action Potential ◽  
Potassium Channel ◽  
Specific Inhibitor ◽  
Genetic Ablation ◽  
Action Potential Prolongation ◽  
Patch Clamp Electrophysiology ◽  
Channel Impairment ◽  
Right Atria ◽  
Α Subunits ◽  
Atrial Repolarization

Voltage-gated Kv1.1 potassium channel α-subunits, encoded by the Kcna1 gene, have traditionally been regarded as neural-specific with no expression or function in the heart. However, recent data revealed that Kv1.1 subunits are expressed in atria where they may have an overlooked role in controlling repolarization and arrhythmia susceptibility independent of the nervous system. To explore this concept in more detail and to identify functional and molecular effects of Kv1.1 channel impairment in the heart, atrial cardiomyocyte patch-clamp electrophysiology and gene expression analyses were performed using Kcna1 knockout ( Kcna1−/−) mice. Specifically, we hypothesized that Kv1.1 subunits contribute to outward repolarizing K+ currents in mouse atria and that their absence prolongs cardiac action potentials. In voltage-clamp experiments, dendrotoxin-K (DTX-K), a Kv1.1-specific inhibitor, significantly reduced peak outward K+ currents in wild-type (WT) atrial cells but not Kcna1−/− cells, demonstrating an important contribution by Kv1.1-containing channels to mouse atrial repolarizing currents. In current-clamp recordings, Kcna1−/− atrial myocytes exhibited significant action potential prolongation which was exacerbated in right atria, effects that were partially recapitulated in WT cells by application of DTX-K. Quantitative RT-PCR measurements showed mRNA expression remodeling in Kcna1−/− atria for several ion channel genes that contribute to the atrial action potential including the Kcna5, Kcnh2, and Kcnj2 potassium channel genes and the Scn5a sodium channel gene. This study demonstrates a previously undescribed heart-intrinsic role for Kv1.1 subunits in mediating atrial repolarization, thereby adding a new member to the already diverse collection of known K+ channels in the heart.

scholarly journals Effect of NIP-142 on Potassium Channel α-Subunits Kv1.5, Kv4.2 and Kv4.3, and Mouse Atrial Repolarization

2010 ◽  
Vol 33 (1) ◽  
pp. 138-141 ◽  
Author(s):  
Hikaru Tanaka ◽  
Iyuki Namekata ◽  
Shogo Hamaguchi ◽  
Taro Kawamura ◽  
Hiroyuki Masuda ◽  
...  
Keyword(s):  
Potassium Channel ◽  
Α Subunits ◽  
Atrial Repolarization

Study of the Characteristics of the Pulmonary Vein and Superior Vena Cava of Rabbits

2021 ◽  
Vol 11 (1) ◽  
pp. 112-122
Author(s):  
Pan Wang ◽  
Xin-Chun Yang ◽  
Xiu-Lan Liu ◽  
Rong-Feng Bao ◽  
Huai-Yu Ding ◽  
...  
Keyword(s):  
Action Potential ◽  
Pulmonary Vein ◽  
Refractory Period ◽  
Potassium Current ◽  
Superior Vena ◽  
Vena Cava ◽  
Current Intensity ◽  
Left And Right ◽  
The Difference ◽  
Right Atria

Background: This study aims to (1) investigate the characteristics of the action potential and triggering activity of cardiomyocytes in the pulmonary vein (PV) and superior vena cava (SVC) of rabbits and (2) study the features of cation currents in cardiomyocytes in rabbit PV and SVC-inward rectifier potassium current (IK1), transient outward potassium current (Ito), and non-selective cation currents (INSCC). Methods: The standard glass microelectrode and whole-cell patch-clamp techniques were used to record the action potential and various currents in the above cells. Results: (1) Cardiomyocytes in either PV or SVC had longer action potential durations than in the adjacent atrium, and spontaneous early after depolarization (EAD) could occur in both PV and SVC under normal physiological conditions. (2) The action potential in PV cardiomyocytes had a relative refractory period but did not have an absolute refractory period, and this characteristic enabled a premature beat that triggered a second plateau response, which led to EAD. (3) INSCC was found for the first time in the PV, SVC, and atria. (4) The current intensity of IK1, Ito, and INSCC was significantly lower in the PV and SVC than in the left and right atria, and the difference in the current intensity in INSCC could influence the action potential. Conclusions: PV and SVC can both initiate and maintain AF, but PV is the primary ectopic foci in initiating AF. The present study found that the second plateau response was easily induced in cardiomyocytes in PA shortly after depolarization. This was a specific characteristic of the action potential of PV. In addition, we preliminarily analyzed the differences in the main outward currents and noted a voltage-dependent INSCC in both PV and SVC rabbits’ cardiomyocytes. Furthermore, the current intensities of IK1, Ito, and INSCC were significantly lower in the PV and SVC than in the left and right atria, and the difference in the current intensity of INSCC influenced the action potential. The different permeability of INSCC for cations at different phases may play a role in inducing EAD.

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.

scholarly journals Comparative gain-of-function effects of the KCNMA1-N999S mutation on human BK channel properties

2020 ◽  
Vol 123 (2) ◽  
pp. 560-570 ◽  
Author(s):  
Hans J. Moldenhauer ◽  
Katia K. Matychak ◽  
Andrea L. Meredith
Keyword(s):  
Action Potential ◽  
Potassium Channel ◽  
Antiepileptic Drug ◽  
Bk Channel ◽  
Gain Of Function ◽  
Double Mutation ◽  
Brain Physiology ◽  
Number Of Patients ◽  
Calcium Activated Potassium Channel ◽  
Channel Properties

KCNMA1, encoding the voltage- and calcium-activated potassium channel, has a pivotal role in brain physiology. Mutations in KCNMA1 are associated with epilepsy and/or dyskinesia (PNKD3). Two KCNMA1 mutations correlated with these phenotypes, D434G and N999S, were previously identified as producing gain-of-function (GOF) effects on BK channel activity. Three new patients have been reported harboring N999S, one carrying a second mutation, R1128W, but the effects of these mutations have not yet been reported under physiological K+ conditions or compared to D434G. In this study, we characterize N999S, the novel N999S/R1128W double mutation, and D434G in a brain BK channel splice variant, comparing the effects on BK current properties under a physiological K+ gradient with action potential voltage commands. N999S, N999S/R1128W, and D434G cDNAs were expressed in HEK293T cells and characterized by patch-clamp electrophysiology. N999S BK currents were shifted to negative potentials, with faster activation and slower deactivation compared with wild type (WT) and D434G. The double mutation N999S/R1128W did not show any additional changes in current properties compared with N999S alone. The antiepileptic drug acetazolamide was assessed for its ability to directly modulate WT and N999S channels. Neither the WT nor N999S channels were sensitive to the antiepileptic drug acetazolamide, but both were sensitive to the inhibitor paxilline. We conclude that N999S is a strong GOF mutation that surpasses the D434G phenotype, without mitigation by R1128W. Acetazolamide has no direct modulatory action on either WT or N999S channels, indicating that its use may not be contraindicated in patients harboring GOF KCNMA1 mutations. NEW & NOTEWORTHY KCNMA1-linked channelopathy is a new neurological disorder characterized by mutations in the BK voltage- and calcium-activated potassium channel. The epilepsy- and dyskinesia-associated gain-of-function mutations N999S and D434G comprise the largest number of patients in the cohort. This study provides the first direct comparison between D434G and N999S BK channel properties as well as a novel double mutation, N999S/R1128W, from another patient, defining the functional effects during an action potential stimulus.

scholarly journals Loss of ATP-Sensitive Potassium Channel Surface Expression in Heart Failure Underlies Dysregulation of Action Potential Duration and Myocardial Vulnerability to Injury

PLoS ONE ◽  
2016 ◽  
Vol 11 (3) ◽  
pp. e0151337 ◽  
Author(s):  
Zhan Gao ◽  
Ana Sierra ◽  
Zhiyong Zhu ◽  
Siva Rama Krishna Koganti ◽  
Ekaterina Subbotina ◽  
...  
Keyword(s):  
Heart Failure ◽  
Action Potential ◽  
Potassium Channel ◽  
Action Potential Duration ◽  
Surface Expression ◽  
Channel Surface
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