scholarly journals Identification of Novel Kv1.3 Blockers Using a Fluorescent Cell-Based Ion Channel Assay

2005 ◽  
Vol 11 (1) ◽  
pp. 57-64 ◽  
Author(s):  
Mark Slack ◽  
Christian Kirchhoff ◽  
Clemens Moller ◽  
Dirk Winkler ◽  
Rainer Netzer
Keyword(s):  
Ion Channel ◽  
Screening Strategy ◽  
Potassium Ion ◽  
Response Analysis ◽  
Potassium Ion Channels ◽  
Fluorescent Cell ◽  
Relationship Analysis ◽  
Electrophysiological Characterization

Afunctional cell-based assaywas developed using a generic proprietary assay protocol, based on a membrane-potential sensitive dye, for the identification of small-molecule antagonists against the Kv1.3 potassium ion channel. A high-throughput screen (HTS) was subsequently performed with 20,000 compounds from the Evotec library, preselected using known smallmolecule antagonists for both sodium and potassium ion channels. Following data analysis, the hit rate was measured at 1.72%, and subsequent dose-response analysis of selected hits showed a high hit confirmation rate yielding approximately 50 compounds with an apparent IC 50 value lower than 10 µ M. Subsequent electrophysiological characterization of selected hits confirmed the initial activity and potency of the identified hits on the Kv1.3 target and also selectivity toward Kv1.3 through measurements on HERG as well as Kv1.3-expressing cell lines. Follow-up structure-activity relationship analysis revealed a variety of different clusters distributed throughout the library as well as several singlicates. In comparison to known Kv1.3 blockers, newchemical entities and scaffolds showing potency and selectivity against the Kv1.3 ion channelwere detected. In addition, a screening strategy for ion channel drug discovery HTS, medicinal chemistry, and electrophysiology is presented.

scholarly journals Crystallization of a potassium ion channel and X-ray and neutron data collection

2019 ◽  
Vol 75 (6) ◽  
pp. 435-438 ◽  
Author(s):  
Patricia S. Langan ◽  
Venu Gopal Vandavasi ◽  
Brendan Sullivan ◽  
Joel Harp ◽  
Kevin Weiss ◽  
...  
Keyword(s):  
Ion Channels ◽  
Ion Channel ◽  
Potassium Ion ◽  
Potassium Ion Channels ◽  
Potassium Ions ◽  
Potassium Ion Channel ◽  
Neutron Data ◽  
Data Set ◽  
X Ray ◽  
Neutron Diffractometer

The mechanism by which potassium ions are transported through ion channels is currently being investigated by several groups using many different techniques. Clarification of the location of water molecules during transport is central to understanding how these integral membrane proteins function. Neutrons have a unique sensitivity to both hydrogen and potassium, rendering neutron crystallography capable of distinguishing waters from K+ ions. Here, the collection of a complete neutron data set from a potassium ion channel to a resolution of 3.55 Å using the Macromolecular Neutron Diffractometer (MaNDi) is reported. A room-temperature X-ray data set was also collected from the same crystal to a resolution of 2.50 Å. Upon further refinement, these results will help to further clarify the ion/water population within the selectivity filter of potassium ion channels.

Pharmacological and electrophysiological characterization of the human bile acid-sensitive ion channel (hBASIC)

2013 ◽  
Vol 466 (2) ◽  
pp. 253-263 ◽  
Author(s):  
Cathérine M. T. Lefèvre ◽  
Alexei Diakov ◽  
Silke Haerteis ◽  
Christoph Korbmacher ◽  
Stefan Gründer ◽  
...  
Keyword(s):  
Bile Acid ◽  
Ion Channel ◽  
Human Bile ◽  
Electrophysiological Characterization

scholarly journals Cell-Based Potassium Ion Channel Screening Using the FluxOR™ Assay

2010 ◽  
Vol 15 (4) ◽  
pp. 441-446 ◽  
Author(s):  
Daniel W. Beacham ◽  
Trillium Blackmer ◽  
Michael O’ Grady ◽  
George T. Hanson
Keyword(s):  
Ion Channel ◽  
High Throughput Screening ◽  
Potassium Ion ◽  
Potassium Ion Channels ◽  
Channel Activity ◽  
Potassium Ion Channel ◽  
Sodium Potassium ◽  
Inhibitory Compounds ◽  
A Cell ◽  
Small Molecule Modulators

FluxOR™ technology is a cell-based assay used for high-throughput screening measurements of potassium channel activity. Using thallium influx as a surrogate indicator of potassium ion channel activity, the FluxOR™ Potassium Ion Channel Assay is based on the activation of a novel fluorescent dye. This indicator reports channel activity with a large fluorogenic response and is proportional to the number of open potassium channels on the cell, making it extremely useful for studying K+ channel targets. In contrast to BTC-AM ester, FluxOR™ dye is roughly 10-fold more thallium sensitive, requiring much lower thallium for a larger signal window. This also means that the assay is carried out in a physiological, normal-chloride saline. In this article, the authors describe how they used BacMam gene delivery to express Kv7.2 and 7.3 (KCNQ), Kir2.1, or Kv11.1 (hERG) potassium ion channels in U2-OS cells. Using these cells, they ran the FluxOR™ assay to identify and characterize channel-specific inhibitory compounds discovered within the library (Tocriscreen™ Mini 1200 and Sigma Sodium/Potassium Modulators Ligand set). The FluxOR™ assay was able to identify several known specific inhibitors of Kv7.2/7.3 or hERG, highlighting its potential to identify novel and more efficacious small-molecule modulators.

Selective Permeability Mechanism of M Type K Channels

2010 ◽  
Vol 96 ◽  
pp. 201-206 ◽  
Author(s):  
Yu Zhi Liu ◽  
Hai Long An ◽  
Jun Wei Li ◽  
Su Hua Zhang ◽  
Yong Zhan ◽  
...  
Keyword(s):  
Ion Channel ◽  
Density Functional ◽  
Neuronal Excitability ◽  
Stochastic Dynamics ◽  
Potassium Ion ◽  
Potassium Ion Channels ◽  
M Current ◽  
Selective Permeability ◽  
The Density Functional Theory ◽  
Dynamics Simulations

M-current plays an important role in the regulation of neuronal excitability and stabilizing the membrane potential. KCNQ2 and KCNQ3 potassium ion channels are proposed to underlie the neuronal M-current. In this paper, we studied the permeable properties and the selective properties of the KCNQ2/3 potassium channel with molecular biology and electrophysiology methods, respectively. Then, based on the first principle and the structure of the KCNQ2/3 potassium ion channel, the potential curve is calculated by the density functional theory. And forced by the potential, the dynamical properties of KCNQ2/3 channels are also studied. Our results, not only from electrophysiology study but also stochastic dynamics simulations, indicate that heteromeric KCNQ2/3 channels all showed a permeation sequence of K+ >Rb+>>Na+. The aim of this research is looking for a possible physical basis for the permeation of ion channel and opens an avenue for further research.

1326Identification of arrhythmic isthmus in patients with transposition of the great arteries treated with atrial switch surgery using a new high-definition wavefront-activation-orientation grid catheter

EP Europace ◽  
2020 ◽  
Vol 22 (Supplement_1) ◽  
Author(s):  
J Francisco Pascual ◽  
S Llerena Butron ◽  
J Perez Rodon ◽  
A Santos Ortega ◽  
B Benito ◽  
...  
Keyword(s):  
High Definition ◽  
Electrophysiologic Study ◽  
Atrial Switch ◽  
Voltage Mapping ◽  
History Of ◽  
Specific Mapping ◽  
Electrophysiological Characterization ◽  
Mapping Catheter

Abstract INTRODUCTION Patients with D- transposition of the great arteries (TGA) treated with Senning or Mustard surgeries have several atrial scars that predispose them to develop atrial tachycardias (AT). Identification of scar zones and possible arrhythmic isthmus in voltage mapping will help to guide the ablation. AIM To describe the feasibility of using a specific mapping catheter to identify possible arrhythmic isthmus in this set of patients. METHODS Prospective observational study in patients with history of SVT and atrial switch surgery, that underwent electrophysiologic study (EP) and electroanatomic (EA) mapping with a new 8Fr deflectable, multipoint wavefront-activation-orientation independent Grid catheter, in a third level hospital since April 2018 until May 2019, with medium-term follow-up. RESULTS A total of 8 EPs were performed in 7 patients (3 (57%) Female, median age 35 ± 6,3 y.o.). Figure 1A shows the localization and percentage of scar identified in both atria. A total of 6 AT were induced. In this, an arrhythmogenic isthmus was identified and, in all patients, at least one non-arrhytmogenic isthmus was documented. Figure 1B shows anatomical and electrophysiological characteristics of the isthmus. Arrhythmogenic isthmus had slower conduction velocity than non-arrhytmogenic ( mean 0,44m/s (IQI 0,17-0,62)  vs  1,05 m/s (IQI 0,86-1,39) p = 0.008) and fractionated potentials were detected more frequently (100% vs 50% p = 0.089) CONCLUSION EA mapping with a new a multipoint, high-definition, Grid Cather is feasible and allows the identification and electrophysiological characterization of arrhythmogenic and non-arrhytmogenic isthmus in patients with TGA treated with atrial switch surgery. Abstract Figure 1

Myrsinane and related diterpenes from Euphorbia falcata with selective potassium ion channel activity

Planta Medica ◽  
2015 ◽  
Vol 81 (16) ◽  
Author(s):  
A Vasas ◽  
P Orvos ◽  
L Tálosi ◽  
P Forgo ◽  
G Pinke ◽  
...  
Keyword(s):  
Ion Channel ◽  
Potassium Ion ◽  
Channel Activity ◽  
Potassium Ion Channel
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