KV4.3 | Shal Related Potassium Channel Member 3

Family:
Potassium channels

Subgroups:
Shaker (K_V1.1–K_V1.8), Shab (K_V2.1-K_V2.2), Shaw (K_V3.1–K_V3.4), Shal (K_V4.1–K_V4.3), KQT like (K_V7.1–K_V7.5), Eag related (K_V10.1-K_V10.2), Erg related (K_V11.1–K_V11.3), Elk related (K_V12.1)

Topology:
Contains six transmembrane domains (S1–S6), four single subunits form a pore, homotetramers and heterotetramers are possible.

KV4.3 Background Information

K_V4.3, 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 (I_to1), the main contributing current to the repolarizing phase 1 of the cardiac action potential. Furthermore it contributes to I_SA 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 384/768i) data and applications:
Cells were kindly provided by Charles River.

Screenshots of the PatchControl 384 software showing K_V4.3 current traces in response to the CiPA voltage step protocol, measured on the SyncroPatch 384PE 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

Icon CE 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, Na_V1.5, Ca_V1.2 and K_V4.3. 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

Icon CE CardioExcyte 96 and SyncroPatch 384PE (a predecessor model of SyncroPatch 384i) 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 384/768i) data and applications:
Cells were kindly provided by Charles River.

Screenshots of the PatchControl 384 software showing K_V4.3 current traces in response to the CiPA voltage step protocol. Measured on the SyncroPatch 384PE using the whole cell patch methodology and multi-hole chips (4 holes per well), the success rate of valuable data for the analysis 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 384i) data and applications:
Cells were kindly provided by Charles River.

Screenshots of the PatchControl 384 software showing K_V4.3/KChIP2 current traces in response to a voltage step protocol and the corresponing 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. The IC₅₀ value of flecanaide was determined as 28.3 µM which is in accordance to literature. The success rate of valuable data for the analysis was 100%.

Application Notes

Cardiac Ion Channels - "Simultaneous Assessment of CiPA Stipulated Ion Channels on the SyncroPatch 384PE"

SyncroPatch 384PE (a predecessor model of SyncroPatch 384i) application note (1.3 MB)
Cells were kindly provided by Charles River.

preview the file here for download

Publications

2015 - Novel screening techniques for ion channel targeting drugs

Patchliner, SyncroPatch 384PE (a predecessor model of SyncroPatch 384i) and Icon CE CardioExcyte 96 publication in Channels (2015)

Authors:
Obergrussberger A., Stölzle-Feix S., Becker N., Brüggemann A., Fertig N., Möller C.