hERG | KV11.1 | Erg Related Potassium Channel Member 2

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.

hERG (KV11.1) Background Information

KV11.1, better known as hERG (human Ether-à-go-go-Related Gene), contributes to the electrical activity of the heart that coordinates the heart's beating (i.e., the hERG channel mediates the repolarizing IKR current in the cardiac action potential). When this channel's ability to conduct electrical current across the cell membrane is inhibited or compromised, either by application of drugs or by rare mutations in some families, it can result in a potentially fatal disorder called long QT syndrome; a number of clinically successful drugs in the market have had the tendency to inhibit hERG, and create a concomitant risk of sudden death, as a side-effect, which has made hERG inhibition an important antitarget that must be avoided during drug development. Due to the documented potential of QT interval prolonging drugs, the United States Food and Drug Administration issued recommendations for the establishment of a cardiac safety profile during pre-clinical drug development: ICH S7B.

hERG has also been associated with modulating the functions of some cells of the nervous system and with establishing and maintaining cancer-like features in leukemic cells.

Gene:
KCNH2

Human Protein:
UniProt Q12809

Tissue:
brain, heart

Function/ Application:
Cardiac IKR current, cell proliferation, cell migration

Pathology:
Long QT syndrome (LQT2), SQT1, atrial fibrillation, sudden infant death syndrome, cancer

Interaction:
KCNH6/ERG2, KCNH7/ERG3, ALG10B, KCNE1, KCNE2, CANX, cAMP, caveolin-1, FHL2

Modulator:
Terfenadine, verapamil, dofetilide, cisapride, astemizole, E4031

Assays:
Patch Clamp: whole cell, room temperature, physiological temperature

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

Cardiomyocytes - Time-dependent effect of Pentamidine on Cor.4U cardiomyocytes

Icon CE   CardioExcyte Cor4U PentamidineCardioExcyte data and applications:
Cells were kindly provided by Axiogenesis.

Time-dependent effect of Pentamidine on Cor.4U cardiomyocytes. Pentamidine clinically causes acquired long QT syndrome, which is associated with prolonged QT intervals, tachycardias, and sudden cardiac arrest. Pentamidine delays terminal repolarization in human heart by acutely blocking cardiac inward rectifier currents. At the same time, it reduces surface expression of the cardiac potassium channel IKr/human ether à-go-go-related gene (hERG).
Insets: EFP raw traces and online analysis value FPDc in the presence of Pentamidine (10 µM) at different timepoints.

hERG - Application of "Sticky Compounds"

application16 herg 2

icon pl   Patchliner data and applications:
hERG expressing HEK293 cells were kindly provided by Cytomyx/Millipore.

Even sticky compounds pose no problem for the Patchliner. IC50 measurements of well known sticky substances were determined on the Patchliner: Terfenadine IC50 = 11.0 ± 3 nM, Flunarizine IC50 163.7 ± 19 nM and Cisapride IC50 8.9 ± 3 nM.

hERG - Block at Physiological Temperature

AppNote hERG TEmp

icon pl   Patchliner data and applications:
Cells were kindly provided by Cytomyx/Millipore, UK.

The effects of erythromycin on hERG currents were tested at different temperatures. Erythromycin has been shown to block hERG channels at physiological temperature with an IC50 of approx. 40 µM. However, at RT erythromycin is much less potent. For more details on these experiments please refer to the Application Note

 

hERG - Current Voltage Relationship

HergIV No and with Leak

icon sp96   SyncroPatch 96 (a predecessor model of SyncroPatch 384PE) data and applications:
Cells were kindly provided by Cytomyx Millipore.

Borosilicate glass chips are used as the patch clamp substrate, ensuring excellent voltage control of the cell membrane and high quality seals. Voltage gated channels such as hERG (expressed in HEK293) have been used to validate the system. These traces show the raw current responses of a single cell to a hERG IV pulse protocol. The data were recorded on the SyncroPatch 96. In the upper screenshot raw current traces are shown. In the lower one the same current traces after leak subtraction are shown.

 

 

hERG - Efficient Screening

p34 2 hERG II Sum

icon pl   Patchliner data and applications:
Cells were kindly provided by Cytomyx/Millipore.

The effects of six different blockers (terfenadine, cisapride, E4031, astemizole, propafenone, quinidine) on hERG currents (HEK293 cells) were investigated. Expected IC50 values for the different compounds were obtained. In two days, 119 full dose response curves were collected by a single person. Data was analyzed using Nanion’s Data Analysis Package, a very efficient and convenient data analysis tool!

hERG - Good Results with "Sticky Compounds"

p14 1 hERG

icon pap   Port-a-Patch data and applications:
Cells were kindly provided by Cytomyx/Millipore.

Sticky compounds, such as some hERG blockers, exhibit expected IC50 values with the Port-a-Patch. The concentrations of the half maximal block were: 1.27 nM (astemizole), 8.9 nM (cisapride), 163.7 nM (flunarizine) and 11.0 nM (terfenadine).

hERG - Pharmacological Experiments at 35 °C

p28 4 fullDoseRespicon pap   Port-a-Patch data and applications:
Cells were kindly provided by Cytomyx/Millipore, UK.

A full dose response curve of quinidine acting on the hERG channel was obtained at physiological temperature (35 °C). The IC50 for quinidine at physiological temperature was 1.3 ± 0.2 μM (n = 5), similar to that obtained at room temperature (1.0 ± 0.03 μM, n = 3).

hERG - Simple Data Analysis

hERG Screenshot Data Analysis Tool 1 700

icon pl   Patchliner data and applications:

With our analysis tools, especially programmed routines in Igor make dose response curves, raw data and current time courses easily accessible. Also, creating average dose response curves over multiple experiments - even conducted on different days - remains easy.

hERG - Stable Recordings

application16 herg 1 small

icon pl   Patchliner data and applications:
Cells were kindly provided by Cytomyx/Millipore, UK.

A series of drug concentrations can be applied to each cell. The top figures show the original traces and the corresponding average dose-response curve. Five concentrations of Quinidine (0.1, 0.3, 1, 3 and 10 μM) have been applied.

The lower figure shows the corresponding Imax (-40 mV) including a wash out step and an additional application of the blocker to demonstrate the stability of whole cell recordings.

 

hERG - Stable Recordings with Accurate Pharmacology

Syncro hERG 2icon sp96   SyncroPatch 384PE data and applications: 
Cells were kindly provided by Charles River Laboratories.

Current-voltage relationship of hERG (Kv11.1) expressed in HEK293 is shown along with pharmacology of 4 hERG-active compounds. The current-voltage relationships for all 384 wells (top) using perforated patch (Escin) and multi-hole chips (4 holes per well) are shown. In all 384 wells, a hERG-mediated current was observed with peak amplitude >700 pA at -20 mV. Using a pharmacology voltage protocol, experiments were stable lasting over 20 minutes. Concentration response curves for astemizole, pimozide, cisapride and terfenadine revealed IC50 values consistent with those found in the literature. 

hERG - Temperature Control

DATA Temp Control small

icon pap   Port-a-Patch data and applications:
Cells were kindly provided by Cytomyx/Millipore.

The image shows example traces for hERG mediated currents at 25 ± 2 °C (black) and 35 ± 2 °C (blue). The peak current amplitude was increased at 35 °C, and the rise time and decay time constants were faster at physiological temperature compared with those obtained at room temperature. 

Application Notes

Cardiac Ion Channels - "High Throughput Screening of Cardiac Ion Channels"

icon sp96   SyncroPatch 384PE   icon pl   Patchliner   Icon CE   CardioExcyte 96 application note   logo pdf   (0.2 MB)

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

icon sp96   SyncroPatch 384PE application note   logo pdf   (1.3 MB)
Cells were kindly provided by Charles River.

Cardiomyocytes - "Combining automated patch clamp, impedance and EFP of hiPSC-CMs"

Icon CE   CardioExcyte 96   icon sp96   SyncroPatch 3984PE   icon pl   Patchliner Application Note 
Cells kindly provided by Takara-Clonetech.

Cardiomyocytes - "Impedance and EFP recordings of Cor.4U cells using Nanion’s CardioExcyte 96"

Icon CE   CardioExcyte 96 Application Note   logo pdf   (1.5 MB)
Cells were kindly provided by Axiogenesis.  

Cardiomyocytes - "Impedance and EFP recordings of iCell Cardiomyocytes² on the CardioExcyte 96"

Icon CE   CardioExcyte 96 Application Note   logo pdf   (2.8 MB)
Cells were kindly provided by Cellular Dynamics.

Cardiomyocytes - "Impedance and EFP recordings of Pluricyte Cardiomyocytes on the CardioExcyte 96"

Icon CE   CardioExcyte 96 Application Note   logo pdf   (1.4 MB)
Cells were kindly provided by Pluriomics.

Cardiomyocytes - "Voltage and current clamp recordings of Cor.4U human iPS cell-derived cardiomyocytes on Nanion’s Patchliner"

icon pl   Patchliner application note:   logo pdf   (0.6 MB)
Cells were kindly provided by Axiogenesis.

hERG - "Characterization of hERG (CHO) on Nanion's Port-a-Patch "

icon pap   Port-a-Patch application note:   logo pdf   (0.6 MB)
Cells were kindly provided by Millipore.  

hERG - "Characterization of hERG (HEK293) on Nanion's Port-a-Patch"

icon pap   Port-a-Patch application note:   logo pdf   (0.7 MB)
Cells were kindly provided by Millipore.  

hERG - "Effect of temperature on erythromycin action on hERG currents recorded on Nanion's Patchliner"

icon pl   Patchliner application note:   logo pdf   (0.9 MB)
Cells were kindly provided by Millipore.

hERG - "High Throughput Pharmacology of hERG Channels on Nanion’s SyncroPatch 384PE"

icon sp96   SyncroPatch 384PE application note   logo pdf   (0.6 MB)

hERG - "Pharmacology of hERG recorded on Nanion´s Port-a-Patch"

icon pap   Port-a-Patch application note:   logo pdf   (0.4 MB)
Cells were kindly provided by Millipore.  

hERG - "Temperature controlled hERG recordings on the Port-a-Patch"

icon pap   Port-a-Patch application note:   logo pdf   (0.5 MB)
Cells were kindly provided by Millipore.  

Testimonials

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Publications

2005 - Cytotoxicity of colloidal CdSe and CdSe/ZnS nanoparticles

icon pap  Port-a-Patch publication in Nano Letters (2005)

2007 - Electrophysiological assessment of HERG blockade: Comparative study using automated and conventional patch clamp systems

icon pap  Port-a-Patch publication in Toxicological Letters (2007)

2009 - Port-a-Patch and Patchliner: High fidelity electrophysiology for secondary screening and safety pharmacology

icon pap  Port-a-Patch and   icon pl   Patchliner publication in Combinatorial Chemistry & High Throughput Screening (2009)

2011 - Automated electrophysiology makes the pace for cardiac ion channel safety screening

icon pl  Patchliner and   icon sp96   SyncroPatch 96 (a predecessor model of SyncroPatch 384PE) publication in Frontiers in Pharmacology (2011)

2011 - State-of-the-art automated patch clamp devices: heat activation, action potentials, and high throughput in ion channel screening

icon pap   Port-a-Patch,   icon pl  Patchliner and   icon sp96   SyncroPatch 96 (a predecessor model of SyncroPatch 384PE) publication in Frontiers in Pharmacology (2011)

2012 - Effects of the Antitussive Drug Cloperastine on Ventricular Repolarization in Halothane-Anesthetized Guinea Pigs

icon pap   Port-a-Patch publication in Journal of Pharmacologigal Sciences (2012)

2012 - Synthesis and In Vitro Antibacterial Activity of Novel 3‐Azabicyclo [3.3. 0] octanyl Oxazolidinones

icon pl   Patchliner publication in Chemical Biology and Drug Design (2012)

2012 - Toward a new gold standard for early safety: automated temperature-controlled hERG test on the Patchliner

icon pl   Patchliner publication in Frontiers in Pharmacology (2012)

2013 - Differential Effects of the β‐Adrenoceptor Blockers Carvedilol and Metoprolol on SQT1‐ and SQT2‐Mutant Channels

icon pap   Port-a-Patch publication in Journal of Cardiovascular Electrophysiology (2013)

2014 - Early identification of hERG liability in drug discovery programs by automated patch clamp

icon pl  Patchliner and   icon sp96   SyncroPatch 384PE publication in Frontiers in Pharmacology (2014)

2014 - New strategies in ion channel screening for drug discovery: are there ways to improve its productivity?

icon sp96  SyncroPatch 384PE publication in Journal of Laboratory Automation (2014)

2015 - Electrophysiological analysis of mammalian cells expressing hERG using automated 384-well-patch-clamp

icon sp96  SyncroPatch 384PE publication in BCM Pharmacology and Toxicology (2015)

2015 - Novel screening techniques for ion channel targeting drugs

icon pl  Patchliner,   icon sp96   SyncroPatch 384PE and   Icon CE   CardioExcyte 96 publication in Channels (2015)

2016 - Automated Patch Clamp Meets High-Throughput Screening: 384 Cells Recorded in Parallel on a Planar Patch Clamp Module

icon sp96  SyncroPatch 384PE publication in Journal of Lab Automation (2016)

2016 - Coupling Data Mining and Laboratory Experiments to Discover Drug Interactions Causing QT Prolongation

icon pl  Patchliner publication in Journal of the American College of Cardiology (2016)

2016 - Myrsinane, Premyrsinane, and Cyclomyrsinane Diterpenes fromEuphorbia falcata as Potassium Ion Channel Inhibitors with Selective G Protein-Activated Inwardly Rectifying Ion Channel (GIRK) Blocking Effects

icon pl  Patchliner publication in Journal of Natural Products (2016)

2017 - Combined Impedance and Extracellular Field Potential Recordings from Human Stem Cell-Derived Cardiomyocytes 

Icon CE  CardioExcyte 96 book chapter in Stem Cell-Derived Models in Toxicology (2017)

2017 - Correlation between human ether-a-go-go related gene channel inhibition and action potential prolongation

icon pl   Patchliner publication in British Journal of Pharmacology (2017)

2017 - Discovery of benzimidazole derivatives as modulators of mitochondrial function: A potential treatment for Alzheimer's disease

icon pl  Patchliner publication in PLoS ONE (2017)

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