Description: potassium voltage-gated channel, subfamily H (eag-related), member 2
Gene: Kcnh2     Synonyms: Kv11.1, ERG1, HERG, LQT2, SQT1, HERG1, KCNH2

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Kv11.1 is encoded by the gene KCNH2, and also known as ERG1; HERG; LQT2; SQT1; HERG1. It is a voltage-activated potassium channel belonging to the eag family. It shares sequence similarity with the Drosophila ether-a-go-go (eag) gene. Mutations in this gene can cause long QT syndrome type 2 (LQT2). Transcript variants encoding distinct isoforms have been identified.

The erg subfamily consists of three members: erg1, erg2 and erg3 [789], [790], [791]. These subunits may form homomultimeric channels, but they are also able to form heteromultimers within their subfamily [792].

Kv11.1 or human-ether-a-go-go-related gene (hERG) underlies the rapid delayed rectifier current, IKr, in the heart that is essential for repolarization of the cardiac action potential and consequently normal cardiac electrical activity and rhythm. In contrast to other Kv channels, hERG channels display unusual gating characteristics, which include slow activation and rapid voltage-dependent inactivation [1515]. With inactivation time constants (in the order of ms) some 1–2 orders of magnitude smaller than the activation time constants (in a range up to hundreds of ms) at the same potential [1508]

Experimental data

Rat Kv11.1 gene in CHO host cell       datasheet
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Rat Kv11.1 gene in HEK host cell
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Rat Kv11.1 gene in CV1 host cell
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RGD ID Chromosome Position Species
621414 4 6192644-6224285 Rat
732102 5 23825407-23857422 Mouse
732101 7 150642049-150675014 Human

Kcnh2 : potassium voltage-gated channel, subfamily H (eag-related), member 2



Acc No Sequence Length Source
NM_053949 n/A n/A NCBI
NM_013569 n/A n/A NCBI
NM_000238 n/A n/A NCBI
NM_172057 n/A n/A NCBI
NM_172056 n/A n/A NCBI



Accession Name Definition Evidence
GO:0005737 cytoplasm All of the contents of a cell excluding the plasma membrane and nucleus, but including other subcellular structures. IEA
GO:0005887 integral to plasma membrane Penetrating at least one phospholipid bilayer of a plasma membrane. May also refer to the state of being buried in the bilayer with no exposure outside the bilayer. IDA
GO:0005886 plasma membrane The membrane surrounding a cell that separates the cell from its external environment. It consists of a phospholipid bilayer and associated proteins. IEA
GO:0005635 nuclear envelope The double lipid bilayer enclosing the nucleus and separating its contents from the rest of the cytoplasm; includes the intermembrane space, a gap of width 20-40 nm (also called the perinuclear space). IEA
GO:0016020 membrane Double layer of lipid molecules that encloses all cells, and, in eukaryotes, many organelles; may be a single or double lipid bilayer; also includes associated proteins. IEA

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Several pharmaceutical drugs target the HERG channel current. Two widely used anti-depressants including escitalopram and citalopram blocked HERG currents in a concentration-dependent manner with an IC50 value of 2.6 μM for escitalopram and an IC50 value of 3.2 μM for citalopram [1515]

Lamotrigine and topiramate

Tail currents, which are purely related to hERG currents, were blocked with IC50 and IC20 (the concentrations when 50% and 20% inhibition was obtained compared to control values) of 229 and 21 microM, respectively, for Lamotrigine. A 35% inhibition of tail currents was obtained at Topiramate concentrations of 1000 microM and a 20% inhibition at 87 microM, respectively [1517]


Kv.11.1 The antianginal drug ranolazine, which combines inhibitory actions on rapid and sustained sodium currents with inhibition of the hERG/IKr potassium channel. Ranolazine inhibited IhERG with an IC50 of 8.03 μM; peak IhERG during ventricular action potential clamp was inhibited ~ 62% at 10 μM [1725]

Mutaion removes hERG block

An S4-S5 linker mutation that allows reactivation of current at hyperpolarized voltages alleviates hERG block, indicating that drugs are trapped in the vestibule by a gate that regulates the permeant path [1519]


Kv.11.1 Block by cisapride requires channel activation. HERG channels were rapidly activated by a 100-ms depolarization step to +60 mV from a holding potential of −80 mV and then clamped to +10 mV for 10 s before tail currents were obtained by repolarization to −50 mV. Control current, current activated by first depolarizing step after a 10-min-long exposure to 100 nM cisapride, and the current obtained after 10 min of drug washout are shown. At −20 mV, 10 nM cisapride reduced HERG tail-current amplitude by 5%, whereas, at +20 mV, the tail-current amplitude was reduced by 45% (n = 4 cells) [1728]


The key residues that seem to interact with NS1643 (1,3-bis-(2-hydroxy-5-trifluoromethyl-phenyl)-urea) are located on the S5 and S6 segments of adjacent subunits and are situated near the pore helix. In all probability, drug bound to this site interferes with the subtle rearrangement of the pore helix/selectivity filter that is believed to underlie P-type inactivation [1521]


RPR260243 has been designated as a type 1 hERG channel activator (Perry et al. 2009). This small molecule enhances current by attenuating inactivation and severely slowing the rate of channel closure (deactivation).

RPR regulates hERG1 and rERG2 differentially

RPR260243 (RPR) induces voltage-dependent slowing of hERG1 deactivation. A study using site-directed mutagenesis proposed the C-linker domain as key component of slow deactivation in ERG channels and found that residues in the C-linker and the adjacent cyclic nucleotide-binding homology domains are sufficient to explain the different sensitivities of hERG1 and rERG2 to RPR.[2091]

Type 2 Activators

hERG channel activators, such as PD118057, its analogue PD307243, NS1643, A935142 and ICA-105574, act primarily to attenuate inactivation and are designated as type 2 activators. Impaired inactivation occurs through a dual mechanism involving both a shift in the voltage dependence of inactivation to more depolarized membrane potentials and a slowing of the onset rate [1523]

α1A and β adrenoceptor (AR)

IKr and hERG current modulation by α1A and β adrenoceptor (AR) stimulation is blocked by inhibitors of protein kinases. Elevating cAMP to directly activate protein kinase A (PKA) causes a positive shift of activation that is removed when four consensus PKA phosphorylation sites on hERG are mutated. Thus, PKA stimulation alters channel function by a mechanism that requires direct phosphorylation of hERG subunits [1520]


KCNE1 and KCNE2 are single transmembrane domain proteins that interact with the pore-forming subunits of KCNQ1 and hERG proteins. Whereas KCNE1 subunits are essential components of the IKs channel complex, the role of KCNEs in regulating Kv11.1 function is still a topic of debate. Both KCNE1 and KCNE2 have been shown to associate with hERG and alter gating kinetics of Kv11.1 both in oocytes and mammalian cell lines. KCNE1 antisense oligos also reduce IKr density in the atrial tumor cell line (AT1 cell). A study in horse heart has provided additional evidence that KCNE1 can coimmunoprecipitate with hERG in native tissue [1733]


hERG potassium channel blockage by scorpion toxin BmKKx2 enhances erythroid differentiation of human leukemia cells K562 [1740]


Chloroquine also slowed the apparent rate of HERG deactivation, reflecting the inability of drug-bound channels to close [1742]

V625A, Y652A and F656A

These mutations decrease the potency of channel block by MK-499 [1742]

Putative hERG-interacting proteins revealed by yeast two-hybrid technique

The yeast two-hybrid technique was used to reveal interacting proteins for the human ERG protein (Kv11.1). Caveolin-1, FHL2 (zinc finger protein) and PTPN12 (a non-receptor tyrosine phosphatase), as well as eight hERG carboxylic terminal-interacting proteins were were identified.[2092]



Protein Synthesis

The human KCNH2 (hERG1) gene is located on the long (q) arm of chromosome 7 at position 36.1 (between base pairs 150,642,043 to 150,675,401) and consists of 15 exons ( Fig. 1A). The Kv11.1 protein is initially synthesized in the endoplasmatic reticulum (ER) as the core-glycosylated precursor form and becomes fully glycosylated in the Golgi apparatus from where the mature form is translocated to the plasma membrane [1518]

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Cartoon and Crystal Structure

Kv.11.1 Like other Kv channels, hERG is formed by coassembly of four α-subunits, each of which has six transmembrane spanning α-helical segments (S1–S6). Within each hERG subunit, the S1–S4 helices form a voltage sensor domain (VSD) that senses transmembrane potential and is coupled to a central K+-selective pore domain. Each pore domain is composed of an outer helix (S5) and inner helix (S6) that together coordinate the pore helix and selectivity filter). The carboxy end of the pore helix and selectivity filter contain the highly conserved K+ channel signature sequence, which in hERG is Thr-Ser-Val-Gly-Phe-Gly. This sequence forms a narrow conduction pathway at the extracellular end of the pore in which K+ ions are coordinated by the backbone carbonyl oxygen atoms of the signature sequence residues. Inactivation gating in hERG and other channels is not fully understood, but is likely to involve subtle conformational changes to the backbone of the selectivity filter (e.g. Stansfeld et al. 2008) that impair K+ ion coordination and block conduction [1523]

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Kv11.1 distribution in Retina

The only study on the localization of Kv11 channel proteins in the retina so far reported an expression of Kv11.1 subunits in somata and primary dendrites of horizontal cells [1734]

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Expression of hERG comparison to other cardiac channel

Compared to Kir2.1 and hEAG, hERG is twice and four times, respectively, more broadly expressed across tissues, tumors, and developmental stages. Importantly, KCNQ1 also exhibits similar levels of expression to hERG in these three EST profile sets. We also caution that these data may represent a conservative estimate, as some examples of negative expression in the hERG EST profile, such as breast tumors, contradict existing functional evidence in these cells

Expression in Rat Brain

All three transcripts are expressed throughout the rat brain: in the olfactory bulb, and erg1 and erg3 are co-expressed in the reticular thalamic nucleus, cerebral cortex, cerebellum and hippocampus [327].

erg subunits can be expressed in different combinations in individual rat lactotroph cells [781].

Transcript location

Transcripts for more than one erg subunit have been detected in various cell lines: NG108-15 (neuroblastoma, erg1–3, [793]), PC12 (sympa- thetic ganglia neuron, erg1 and erg2, [327]), MMQ (lactotroph, erg1–3, [794]) and GH3/B6 (somatomam- motroph, erg1 and erg2, [795]).

Tissue distribution of herg1

Kv.11.1 the erg1 gene is expressed abundantly in brain and in retina. Intriguingly, given the clinical symptoms associated with mutations in the erg1 gene, erg1 mRNA is expressed abundantly in sympathetic ganglia. This result suggests that mutations in the erg1 gene could affect sympathetic regulation of cardiac function in addition to having direct effects on myocardial function [790]

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Cardiac Repolarization

Human ether-a-go-go-related gene (hERG) potassium channels conduct the rapid component of the delayed rectifier potassium current, IKr, which is crucial for repolarization of cardiac action potentials. Moderate hERG blockade may produce a beneficial class III antiarrhythmic effect. In contrast, a reduction in hERG currents due to either genetic defects or adverse drug effects can lead to hereditary or acquired long QT syndromes characterized by action potential prolongation, lengthening of the QT interval on the surface ECG, and an increased risk for "torsade de pointes" arrhythmias and sudden death [1842]

Volume and Na2+ Regulation

Rat ERG channels have also been identified in the kidney, where they display heterogeneous subcellular localization according to nephron segment66. Here, the channel function may be related to volume regulation and osmotic balance during sodium transport [1730]

Fetal development

In addition to regulating LQTS in adults, hERG, like other potassium channels83, appears to have an important role in development. Data derived from mutational analyses of an Arabian family with frequent miscarriages suggests that homozygous nonsense mutations in the channel may be associated with embryonic lethality15. Functional experiments based on this genetic analysis highlight the nonsense-mediated decay of the hERG transcript and subsequent neonatal arrhythmias as a potential mechanism for this recurrent fetal loss [1731]

Erg (eag-related) channels play critical roles in regulating the resting membrane potential [780],[781], action potential duration [782], spike frequency adaptation and hormone secretion [781]. Due to a Per-Arnt-Sim domain in the N-terminus of erg channel subunits, even a role in O2-sensing has been discussed [783].

Long and Short QT Syndrome and other Diseases

Herg channel is associated with numerous diseases including tumours, Epilepsy, Cardiovascular disease, Schizophrenia, QT syndrome and Muscular dystrophy [1732]

Labour Contractions

Diminished hERG K(+) channel activity facilitates strong human labour contractions but is dysregulated in obese women [1754]

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Biophysical Properties of HERG in CHO-K1


Whole-cell voltage clamp recordings of HERG-transfected cells revealed currents (‘HERG currents') with biophysical properties similar to those reported by previous investigators. Current-voltage relations and activation kinetics were determined using step depolarizations to potentials between −35 and +25 mV from a holding potential of −55 mV (Figure 1b). Activating current amplitude increased with voltage to a maximum at −5 mV (Figure 1c), then declined at more positive potentials due to strong inward rectification.

Effects of Temperature on hERG channel in CHO cells

Kv.11.1 Increased functional expression of hERG at 30°C. HERG-expressing CHO cells were grown at 37°C (Materials and Methods), and then split and kept subconfluent at either 37 or 30°C for 3 d. Voltage command protocol (A). HERG currents were averaged from the last 200 mS of the -30 mV inactivation step before compound addition, subtracting the same recording after the application of 10 μM dofetilide. Patch clamp recordings made with an IonWorksHT instrument from a representative cell maintained at either 37 or 30°C (B,C, respectively). The black traces are recordings before compound addition. The grey traces are recordings following 10 μM dofetilide addition. It is noticeable that the difference at the initial phase of the -30 mV step was even bigger between the two temperatures [1848]

Inward Rectification

The different physiological roles of erg channels are enabled by their peculiar gating [778]. Although they are voltage-gated K+ channels constructed of subunits with six transmembrane domains, functionally, erg channels are inward rectifiers. This inward rectification is due to fast inactivation kinetics combined with slow activation as well as fast recovery from inactivation combined with slow deactivation [784], [785], [786], [787], [788].


Stimulation of PKC with 1-oleoyl 2-acetylglycerol (OAG), decreased current amplitudes in a concentration dependent manner (pIC50 = 5.9 ± 0.1, n ≥ 4) [1520]

β9-strand Replacement

Replacement of the predicted β9-strand in Kv11.1 cNBH domain (860-FNL-862) with alanine residues not only destabilizes the open state relative to the closed state (fig2), it also destabilizes the inactivated state relative to the open state [1522]

RPR260243 has been designated as a type 1 hERG channel activator (Perry et al. 2009). This small molecule enhances current by attenuating inactivation and severely slowing the rate of channel closure. By contrast, PD118057 binds closer to the selectivity filter, forming intersubunit interactions between the pore helix and S6 that shifts the voltage dependence of inactivation to more depolarized potentials [1523]

Temperature effect on mutated hERG expression

Kv.11.1 Effect of temperature on cell surface membrane expression of the N470D mutation. A, patch clamp recordings of HERG current from N470D transfected cells cultured at 37 or 27 °C. HERG current was activated by 4-s-long depolarizing steps between −70 and 50 mV in 10-mV increments from a holding potential of −80 mV. Cells were then clamped to −60 mV for 6 s to record tail current. The N470D mutation produced increased HERG current when cultured at 27 °C. In addition, low temperature treatments not only markedly rescue the expressions of most trafficking-deficient mutants of Kv11.1 (human ether-a-go-go related gene; hERG) channels, but also improve the expression of its wild-type (WT) channels [1727]

Impact of temperature and voltage protocols in HERG channels

The impression from previous studies using oocytes and mammalian cell lines was that the changes in the gating behaviors and current density of HERG channel at higher temperature poise channels more sensitive to HERG blockers such that lower IC50 values were more likely to be obtained at physiological temperatures. by changing temperature from 22 °C to 35 °C, the alteration in potency of the compounds tested was diversified: for E-4031 the potency was unchanged, for ketoconazole it was slightly increased, and for astemizole it was decreased. The reason for the lower apparent potency of astemizole at near-physiological temperature is not clear. It is possible that: (1) astemizole blocks the opened channels more powerfully than it blocks the inactivated channels, and at the high temperature, acceleration of transition from the open state to inactivated state leads to a shortening of period that the drug interacts with the opened channels; and (2) astemizole has less time to interacts with channels at the open/inactivated states at 35 °C since the duration of Vt in high-temperature protocols (2 s) is much shorter than that in the standard protocol (5 s). These results suggest that the mechanisms underlying the impact of temperature may vary greatly, depending on the alterations in drug–channel interactions at different temperatures [1739]

Single Channel of Herg in CHO cells

Kv.11.1 The depicted traces illustrate the three types of recordings observed: (i) no channel openings, (ii) early openings, and (iii) late channel openings during the depolarization step. B: average of 32 traces from patches that had at least four channels in the patch. Note the hooked tail current recorded at −120 mV, similar to that seen in whole cell currents [1733]

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The continuous-time Markov state model was phrased as a system of non-autonomous ordinary differential equations along with an algebraic equation representing the conservation of states property of Markov chains. Each state transition is described by a forward rate: α =α0 exp[zαVm/(RT/F)] and a backward rate: β =β0exp[-zβVm/(RT/F)], where R is the universal gas constant, T is the absolute temperature and F is Faraday's constant [1701]


Kv.11.1 (Cx = closed states. O = open state. I = inactivated state. OD = drug bound to open state. ID = drug bound to inactivated state. Greyed out portions of the model were not altered during modelling simulations.) The Markov chain model for Kv11.1 kinetics is based on that developed by Lu et al 2001, with the addition of two states: drug-bound open state and drug-bound inactivated state. The rate constants from were scaled to 22◦C [The Kinetics and State Dependence of Drug Binding to Kv 11.1, MJ Perrin 2009]


Models of hERG gating. A: Markov state descriptions of hERG kinetics: (i) linear scheme, (ii) branched scheme, (iii) subunit scheme, and (iv) relaxed-activated state scheme. B: action potentials (top panel) and Kv11.1 currents (bottom panel) simulated using different hERG gating models. In each case, the Hodgkin-Huxley formulation of the IKr component in the ten Tusscher description of the ventricular action potential was replaced with the model shown. For comparison, the maximum IKr conductance was equivalent in each case. Simulations were carried out at 37°C. Where models were derived from data at different temperatures, rate constants were corrected using a Q10 of 3.3 [1733]



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Mitcheson JS et al. Trapping of a methanesulfonanilide by closure of the HERG potassium channel activation gate.
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Narayana Moorthy NS et al. Human ether-a-go-go-related gene channel blockers and its structural analysis for drug design.
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Contributors: Nitin Khanna

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