KV4.3 | Shal Related Potassium Channel Member 3
Family:
Potassium channels
Subgroups:
Shaker (KV1.1–KV1.8), Shab (KV2.1-KV2.2), Shaw (KV3.1–KV3.4), Shal (KV4.1–KV4.3), KQT like (KV7.1–KV7.5), Eag related (KV10.1-KV10.2), Erg related (KV11.1–KV11.3), Elk related (KV12.1)
Topology:
Contains six transmembrane domains (S1–S6), four single subunits form a pore, homotetramers and heterotetramers are possible.
KV4.3 Background Information
KV4.3, a voltage-activated A-type potassium ion channel, is prominent in the repolarization phase of the action potential and contributes to the cardiac transient outward potassium current (Ito1), the main contributing current to the repolarizing phase 1 of the cardiac action potential. Furthermore it contributes to ISA currents in neurons.
Gene:
KCND3
Human Protein:
UniProt Q9UK17-1, Q9UK17-2 (two different isoforms encoded by alternatively spliced transcript variants of the gene)
Tissue:
Heart, brain
Function/ Application:
repolarization of action potentials
Pathology:
Brugada Syndrome 9 (gain of function mutation), Spinocerebellar Ataxia 19, autosomal dominant inheritance, cerebellar atrophy, cognitive impairment, cogwheel rigidity, dysarthria
Interaction:
Homotetramer or heterotetramer with KCND1 and/or KCND2. Associates with the regulatory subunits KCNIP1, KCNIP2, KCNIP3 and KCNIP4, KCNE1, KCNE2, SCN1B, SRC, KCNAB1 and DLG1
Modulator:
4-AP, imipramine, E-4031, amitriptyline, disopyramide, XE 991 dihydrochloride
Assays:
Patch Clamp: whole cell
Recommended Reviews:
Gutman et al. (2005) International Union of Pharmacology. LIII. Nomenclature and molecular relationships of voltage-gated potassium channels. Pharmacol Rev 57(4):473-508
Data and Applications
KV4.3 - Pharmacology of Metropolol Tartrate, using the CiPA Protocol
SyncroPatch 384/768 PE (a predecessor model of SyncroPatch 384) data and applications:
Cells were kindly provided by Charles River.
Screenshots of the PatchControl 384 software showing KV4.3 current traces in response to the CiPA voltage step protocol, measured on the SyncroPatch 384PE (a predecessor model of SyncroPatch 384) using the whole cell patch methodology and single-hole chips. The IC50 value of Metropolol Tartrate was determined as 128 µM.
Cardiac Ion Channels - Pharmacology of Vandetanib
CardioExcyte 96 and 
Patchliner data and applications:
Cells were kindly provided by Charles River and Cellular Dynamics.
The image on the left hand side displays the results of the blocking effect of Vandetanib on hERG, NaV1.5, CaV1.2 and KV4.3. The compound induced arrhythmia when iPSC-CM were exposed to a minimum concentration of 1 µM. Arrhytmic events were both detected in field potential recordings as well as in the impedance based contractility.
Cardiac Ion Channels - Pharmacology of Sotalol
CardioExcyte 96 and SyncroPatch 384PE (a predecessor model of SyncroPatch 384) data and applications:
Cells were kindly provided by Charles River and Cellular Dynamics.
The image on the left hand side displays the results of the blocking effect of Sotalol on hERG. The result is in good agreement with manual patch clamp data (Crumb et al., 2016). The compound induced arrhythmia when iPSC-CM were exposed to a minimum concentration of 10 µM. Arrhytmic events were both detected in field potential recordings as well as in the impedance based contractility measurements.
KV4.3 - Pharmacology of Quinidine
SyncroPatch 384/768 PE (a predecessor model of SyncroPatch 384) data and applications:
Cells were kindly provided by Charles River.
Screenshots of the PatchControl 384 software showing KV4.3 current traces in response to the CiPA voltage step protocol. Measured on the SyncroPatch 384PE (a predecessor model of SyncroPatch 384) using the whole cell patch methodology and multi-hole chips (4 holes per well), the success rate of completed experiments was 95.3%. The IC50 value of Quinidine was determined as 21.2 µM (Literature: 79.3 µM, Crumb et al., J Pharmacol Toxicol Methods. 2016).
KV4.3/KChIP2 - Dose-response curve of Flecanaide
SyncroPatch 384PE (a predecessor model of SyncroPatch 384) data and applications:
Cells were kindly provided by Charles River.
Screenshots of the PatchControl 384 software showing KV4.3/KChIP2 current traces in response to a voltage step protocol and the corresponding current-voltage relationship plot. Using whole cell mode in combination with multi-hole chips (4 holes per well), stably transfected cells were measured on the SyncroPatch 384PE (a predecessor model of SyncroPatch 384). The IC50 value of flecainide was determined as 28.3 µM which is in accordance to literature. The success rate of completed experiments was 100%.
Application Notes
Cardiac Ion Channels - "Simultaneous Assessment of CiPA Stipulated Ion Channels on the SyncroPatch 384PE"
SyncroPatch 384PE (a predecessor model of the SyncroPatch 384) application note 
(1.3 MB)
Cells were kindly provided by Charles River.
Posters
2018 - High throughput automatic patch clamp: Applications for Safety Pharmacology
SyncroPatch 384PE (a predecessor model of the SyncroPatch 384) poster, JSPS Meeting 2018 (2.3 MB)
2017 - Cardiomyocytes in Voltage Clamp and Current Clamp by Automated Patch Clamp
SyncroPatch 384PE (a predecessor model of the SyncroPatch 384) and Patchliner poster, BPS Meeting 2017 (1.7 MB)
2015 - High Throughput Automated Patch Clamp of Ion Channels Important in Cardiac Safety and Drug Discovery
SyncroPatch 384PE (a predecessor model of SyncroPatch 384) poster, Chantest Meeting 2015 (1.9 MB)
Presentations
2017 - HTS in Cardiac Safety
CardioExcyte 96 presentation (slide deck) (4.0 MB)
2018 - HTS Phase I study: an update on progress of the CiPA Ion Channel Work Stream using the SyncroPatch 384PE and Patchliner
SyncroPatch 384PE (a predecessor model of the SyncroPatch 384i), Patchliner and CardioExcyte 96 Oral Presentation
Presenter:
Tim Strassmaier, Nanion Technologies Inc. USA
Source:
Webinar: "CiPA study: Bridging ion channel and myocyte data", September 12, 2018
Publications
2019 - A Kinetic Map of the Homomeric Voltage-Gated Potassium Channel (Kv) Family
Patchliner publication in Frontiers in Cellular Neuroscience (2019)
Authors:
Ranjan R., Logette E., Marani M., Herzog M., Tâche V., Scantamburlo E., Buchillier V., Markram H.
2015 - Novel screening techniques for ion channel targeting drugs
Patchliner, SyncroPatch 384PE (a predecessor model of SyncroPatch 384i) and CardioExcyte 96 publication in Channels (2015)
Authors:
Obergrussberger A., Stölzle-Feix S., Becker N., Brüggemann A., Fertig N., Möller C.