Acta Pharmacologica Sinica (2013) 34: 329–335
© 2013 CPS and SIMM All rights reserved 1671-4083/13
hERG channel function: beyond long QT
Joseph J BABCOCK, Min LI*
Department of Neuroscience, High Throughput Biology Center and Johns Hopkins Ion Channel Center (JHICC), School of Medicine,
Johns Hopkins University, 733 North Broadway, Baltimore, MD 21205, USA
To date, research on the human ether-a-go-go related gene (hERG) has focused on this potassium channel’s role in cardiac repolar-
ization and Long QT Syndrome (LQTS). However, growing evidence implicates hERG in a diversity of physiologic and pathological pro-
cesses. Here we discuss these other functions of hERG, particularly their impact on diseases beyond cardiac arrhythmia.
Keywords: long QT; hERG; cardiotoxicity; cancer; potassium channel
Acta Pharmacologica Sinica (2013) 34: 329–335; doi: 10.1038/aps.2013.6
The human ether-a-go-go related gene (hERG) encoded potas-
sium channel has generated considerable scientific interest
due to its role in genetically and pharmacologically linked
arrhythmias[1, 2]. Admittedly, promiscuous block of cardiac
hERG channels by a variety of structurally different drugs rep-
resents a major research question and a therapeutic challenge,
which has profound impacts on human health. However, its
initial discovery was prompted not by cardiac phenomena
but by a neurologic phenotype in Drosophila, in which muta-
tion of the homologous Eag gene leads to spasmodic leg
move ments[3, 4]. Judging by the number of PubMed articles
obtained by a search for ‘hERG’ and ‘heart’ (627) in compari-
son to ‘cancer’ (107), ‘brain’ (92), or ‘pancreas’ (4), function of
the channel in the nervous system is but one of many topics
less prevalent than Long QT Syndrome (LQTS) research. In
this perspective we survey existing evidence for hERG expres-
sion and function in the other tissues, many of which are
linked to disease. Whether its roles are causal or not, these
suggest therapeutic opportunities beyond the cardiac system.
Surveying hERG gene expression
To examine primary evidence for hERG expression in non-
cardiac tissues, we utilized NCBI Unigene EST profiles.
Previous analyses have suggested that this type of dataset con-
tains fewer false negatives than microarrays[6, 7], an appealing
characteristic for a broad survey. The results are displayed in
Figure 1A, which compares hERG expression to that of three
other potassium channels, KCNQ1, Kir2.1 (KCNJ2) (both also
expressed in the heart and genetically linked to LQTS) and
hEAG (an EAG family member also expressed in cancers).
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 conser-
vative estimate, as some examples of negative expression in
the hERG EST profile, such as breast tumors, contradict exist-
ing functional evidence in these cells[8, 9].
We also explored information concerning differential
expression (DE, significant up- or down-regulation), accord-
ing to microarray and RNA-Seq meta-analyses in the EBI Gene
Expression Atlas. The results in Figure 1B, like the Unigene
profiles, indicate a diversity of tissues and diseases in which
hERG is differentially expressed. Intriguingly, even though
the metric compared (absence/presence versus DE) is differ-
ent in the Unigene EST and EBI Gene Atlas data, the relation-
ship between the hERG, KCNQ1, Kir2.1, and hEAG profiles
remains similar. While hERG and KCNQ1 demonstrate simi-
lar levels of DE across all samples types, Kir2.1 and hEAG
have fewer observed cases of DE in the same rank order as
the EST data. While a more systematic analysis is outside the
scope of this article, we speculate that the similarity in patterns
between the presence/absence (EST profiles) and DE (Gene
Atlas) data might be explained by more broadly expressed
genes possessing greater ‘opportunity’ for modulation in vari-
ous diseases or physiological processes.
For each of the tissue types annotated for hERG expres-
sion by the EST profile, additional existing evidence through
expression, functional studies, or pathologic links are summa-
* To whom correspondence should be addressed.
Received 2012-12-07 Accepted 2012-01-19
Babcock JJ et al
Acta Pharmacologica Sinica
rized in Table 1.
Roles in cancer
In addition to signaling in the mammalian nervous system,
growing evidence shows changes in membrane potential occur
during cellular differentiation and cell cycle progression[45, 46].
Thus, it is perhaps unsurprising that changes in the expression
of voltage-sensitive channels such as hERG have been reported
in cancer, a disease associated with disregulated cellular pro-
liferation. The initial study implicating hERG in oncogenesis
utilized both Northern blot probes and patch clamps to iden-
tify functional expression of the channel in 17 tumor types
derived from diverse cell lineages. Because corresponding
non-pathological tissues for these tumors lacked expression of
hERG, the authors proposed that the depolarization resulting
from channel over-expression might confer a selective advan-
tage for survival in hypoxic environments. Additional
functional evidence for this interpretation is that Imatinib (a
known channel blocker) decreases VEGF secretion in leuke-
mic cells expressing hERG, which could inhibit the growth
of endothelial vasculature that supports tumor viability.
Additional experiments studying pharmacological inhibi-
tion by E4031 (a type III antiarrhythmic and selective channel
blocker) have suggested that hERG expression may facilitate
cell migration in diverse hematopoetic neoplasms through an
integrin-associated signaling pathway[17, 19, 23]. Further, hERG
has also been identified in microvesicles shed by leukemic
cells. These microvesicles up-regulate hERG expression in
non-neoplastic cells when incorporated in the cell membrane,
a feedback mechanism that thus exerts pleiotropic effects
through vesicular trafficking.
In some cancer cell lines, the pharmacological cross-reac-
tivity of hERG and other targets complicates interpretation
of its function. This is demonstrated by experiments using
MCF-7 breast cancer cells, in which application of the selective
inhibitor E4031 has identified a distinct role for hERG in vol-
ume regulation that is separate from the proliferation medi-
ated by the closely related human ether-a-go-go gene (hEAG)
potassium channel. These proliferative effects are blocked
by astemizole, which is known to inhibit both hEAG and
hERG, while caspase-3 dependent apoptosis may be initiated
by the similarly nonspecific effects of arsenic trioxide. Taken
together with previous evidence that associates genetically
linked LQTS with mutations in at least eleven genes, includ-
ing other potassium, calcium, and sodium channels[47, 48], such
data suggest that compounded effects on hERG and other
ion-conductive proteins might not be easily separated with
nonselective modulators. Indeed, blockade of multiple classes
of ion channels may have synergistic effects on tumor growth,
as suggested by prostate cancer experiments in which amio-
darone (a K+, Ca2+, and Na+ channel blocker) is more potent
than compounds that block only two ion channel classes.
Furthermore, natural products such as berberine are thought
to have effects not only on multiple ion fluxes, but also on
other oncogenic pathways, thereby complicating the inter-
pretation of their anti-migratory activity in hERG-expressing
AML cells. Additionally, hERG functions in one tissue
may be associated with different channels in others. Indeed,
in medullablastomas similar volume regulation, as discussed
above, has been linked to the EAG2 channel rather than
hERG. Conversely, the specific inhibitors E4031 and WAY
have been shown to mediate apoptotic and anti-proliferative
effects in leukemia, effects that appear independent of hERG in
other tumors. However, given that the non-selective inhibi-
tor ranolazine (which blocks voltage-gated sodium channels
as well as hERG) also inhibits leukemia proliferation,
the effects of blocking multiple ionic currents may be tissue-
The particular cell cycle defects associated with hERG
expression may also vary between neoplasms of different
tissue origin. Experiments in gastric and ovarian carcino-
mas suggest that channel function is associated with S-phase
transition or accumulation[36, 41], while in endometrial cancers
activity appears to be correlated with occupancy of the G2/M
phase. Cell cycle dependent patterns of channel expression
add further complexity to hERG’s role in SH-SY5Y neuroblas-
toma cells. Furthermore, it remains unclear whether hERG
expression in cancerous cells (or nervous system disorders,
as discussed below) represents a downstream consequence of
general pathologic processes such as inflammation. Evidence
for the modulation of hERG expression by inflammation
includes down-regulation following ceramide-induced TNF-α
signaling, as well as changes following pro-inflammatory
arsenic or mercury treatment[57, 58]. Analogously, data from
Figure 1. Diversity of tissue expression and regulation of cardiac
potassium channels. A) The fraction of samples expressing (gene
present/absent) hERG (KCNH2), KCNQ1, Kir2.1 (KCNJ2), or hEAG (KCNH1)
channels in Unigene EST profiles for tissues, tumors, and developmental
stages. Parentheses indicate the number of samples in each profile
class. B) The number of EBI Gene Expression Atlas experiments
showing differential expression (transcript regulated up/down) of cardiac
potassium channels across five experimental classes.
Babcock JJ et al
Acta Pharmacologica Sinica
leukemia suggest that hERG expression may be induced in
a dose-dependent manner by chemokine SDF-1a, a consti-
tutively active stromal signaling factor. As well as being
downstream of other signals, hERG expression may conceiv-
ably be coordinately regulated with other tumor biomarkers
such as the hEAG channel[36, 51], TNFR1, or CXCR4. Given
these mechanisms, the induction of inflammation-associated
genes in schizophrenia and epilepsy suggests the possibil-
ity that channel expression might also be induced in neuro-
logic conditions as a secondary consequence of tissue damage
in the nervous system.
In contrast to the examples given above, where the absence
of the channel in normal tissues suggests its expression might
serve as a biomarker for cancer, the expression of hERG in
Table 1. hERG function and pathology classified by tissue type.
Tissue Cell types/cell lines Expression evidence Functional evidence Biological role Disease linkage Reference
[17, 20, 23]
[8, 9, 27]
Primary, rat PC12
Primary, Ehrlich tumor
K652, U937, HL-60, CEM,
Raji, peripheral blood
Renal cell carcinoma,
SW2 cell line, A549 cell
Primary, α+β islet cells
tissue, GH3 cells
SGC7901, AGS, MGC803,
and MKN45 cells
Endometrium tissue, AN3-
CA, KLE, Ishikawa, C-33A,
MS-751, and QG-U)
RT-PCR, Western blot,
RT-PCR, Western blot,
Western blot, Unigene
RT-PCR, Western blot,
mRNA, protein, Unigene
RT-PCR, Unigene EST
RT-PCR, Unigene EST
E4031 and WAY-123
E4031, arsenic trioxide
E4031 , Imatinib
apoptosis, VEGF secretion,
Therapeutic action of
Rhythmic oscillations in
Glucagon and glucose
G2/M cell cycle occupany
Small cell lung
Babcock JJ et al
Acta Pharmacologica Sinica
some tumors may reflect a non-pathogenic role. For example,
prolactin secretion in adenomas derived from the pituitary
gland is dependent upon hERG expression. There is also
evidence that the channel may not always mediate cancer
itself, but rather the physiologic response to the disease. For
instance, the murine homologue of hERG is up-regulated in
the skeletal muscles of mice whose mobility is reduced due to
wasting and inactivity following tumor injection. This up-
regulation subsequently appears to induce muscular atrophy
by activating the ubiquitin proteasome system.
Digestive, secretory, and reproductive systems
Like the heart, the mammalian digestive, secretory, and repro-
ductive systems require electrically coupled contractions. This
similarity to cardiac repolarization logically supports a role for
hERG in these systems. Indeed, immunohistochemical and
pharmacological data argue for the expression of functional
hERG channels in both the longitudinal smooth muscles and
the enteric neurons of the human small intestine. These
results parallel earlier studies that correlated phasic contrac-
tions in the rat stomach with activity of hERG homologues,
suggesting that this role was conserved through evolution.
Further, the pH sensitivity of the channel may provide a
molecular link for regulating electrical signaling through the
acidity of the gastrointestinal lumen. Channel activity may
also explain the cramps and diarrhea caused by antibiotics
such as erythromycin, which is a known blocker of hERG.
Rat ERG channels have also been identified in the kidney,
where they display heterogeneous subcellular localization
according to nephron segment. Here, the channel function
may be related to volume regulation and osmotic balance dur-
ing sodium transport. In the human and mouse pancreas,
ERG expression and functional currents have been identified
in α and β islet cells. Pharmacological antagonism of the
channel in these cells appears to enhance glucose and argin-
ine-induced insulin secretion and repress glucagon secretion
under low glucose conditions by modulating transmembrane
calcium fluxes[37, 38].
In mice, contractions of the uterus in early pregnancy may
be enhanced or suppressed by chemical activators or inhibi-
tors of ERG. However, this activity is lost in later preg-
nancy, during which other voltage-gated potassium channels
of the Kv7 family appear to play a role. Bovine homologues
of hERG appear to also regulate rhythmic contractions in the
male reproductive system, as inhibitors such as E4031, halo-
peridol, and cisapride increase movements of the epididymis
that facilitate passage of sperm. In this context, the channel
appears to regulate extracellular calcium influx, as the activity
is not sensitive to thapsigargin treatment. The movement
of rat sperm in the epididymal tract is similarly accelerated by
the potassium channel blocker sibutramine, although whether
this is due to the activity of the rat ERG channel remains
Signaling and disease in the nervous system
As previously noted, ERG expression was initially identified
in both the mammalian hippocampus and the heart. Spas-
modic motor system signaling that is caused by mutations of
the Drosophila ERG channels is reminiscent of the epilepsies
that are linked to defects in expression or function of mamma-
lian voltage-gated Kv7 (KCNQ) channels[3, 72]. Although Kv7
channels have been associated with both cardiac arrhythmias
and a variety of brain diseases[47, 72], hERG channels have only
recently been associated with diseases of the central nervous
system. Expression of a short brain-specific isoform of hERG
has been associated with schizophrenia, while sequence
variants may correlate with the efficacy of antipsychotic medi-
cations in patients[24, 73]. Analysis identifying the statistically
significant co-occurrence of LQTS and epilepsy further impli-
cates the hERG channel in neurologic diseases.
Evidence for the non-pathologic role of ERG channels in
the mammalian nervous system has come from in vitro and
in vivo studies in rat and mouse. In mice, functional ERG
channels have been identified in brain slices derived from the
medial nucleus of the trapezoid body (MNTB) of the auditory
brainstem. Hyperexcitability resulting from E4031 or terfen-
adine treatment in these slices offers an intriguing mechanism
for reports linking LQT events to sudden auditory stimuli.
Functional ERG channels have also been identified in murine
mitral/tufted cells of the olfactory bulb, indicating that they
may be important in regulating excitability in multiple sen-
sory organs. In the cerebellum, ERG channels appear to
be involved in the control of membrane potential and firing
frequency adaptation of Purkinje neurons. During develop-
ment, expression in GABAergic neurons of the spinal cord has
been implicated in circuit maturation. Data from rats have
also suggested a role for ERG channels in hippocampal γ oscil-
lations, and that they are regulated by thyrotropin-releasing
hormone (TRH) signaling in the anterior pituitary gland[79, 80].
In chromaffin cells, ERG activity appears to modulate epi-
nephrine secretion, offering a possible connection between
LQTS and catecholaminergic signaling. In midbrain dop-
amine neurons, hERG blockers have been shown to limit
depolarization inactivation, and thus may have therapeutic
benefit for psychiatric diseases associated with defects in dop-
amine signaling. Beyond neurons, ERG channels have also
been identified in rat microglia.
Roles in development
In addition to regulating LQTS in adults, hERG, like other
potassium channels, 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 asso-
ciated with embryonic lethality. Functional experiments
based on this genetic analysis highlight the nonsense-medi-
ated decay of the hERG transcript and subsequent neonatal
arrhythmias as a potential mechanism for this recurrent fetal
Pharmacologically, hERG-blocking drugs may induce
embryonic ischemia by impairing cardiac activity. This
harmful effect is amplified when blood flow is restored due
Babcock JJ et al
Acta Pharmacologica Sinica
to the generation of reactive oxygen species (ROS), which
can lead to developmental abnormalities, such as cleft
palate defects or ventricular malformations observed in rat
models[28, 85]. Similar teratogenic effects have been reported
for other medications including erythromycin, almokalant,
dofetilide, phenytoin, cisapride, and astemizole[84, 86]. Further,
it has been demonstrated that progesterone may modulate
hERG folding in the ER and Golgi trafficking by regulating
intracellular cholesterol homeostasis, thus offering a possible
mechanism for arrhythmic risk in late-stage pregnancy.
Although hERG has received attention primarily because of its
role in LQTS, our survey highlights the diverse biological and
pathogenic roles of the channel. These studies have been cata-
lyzed by the availability of pharmacological agents for hERG
channels. This rich functional repertoire has implications for
translational research, as potential chemotherapeutic or anti-
schizophrenic effects of known blockers must be balanced
by consequent concerns for cardiac safety. Indeed, patients
who have experienced severe LQT-caused cardiac conditions
often also have other complicating life style factors or health
conditions. Therefore, LQTS and other medical conditions
caused by or linked to hERG cannot readily be separated. In
some instances, cardiac side effects may be mitigated by com-
pensatory modulation[88–90]. The promiscuity of drug-channel
interactions that is unique to hERG also raises the question of
whether there is a much broader but less well characterized
impact on health by drugs that are capable of inhibiting hERG
currents in non-cardiac cells.
We also note that the majority of activities summarized
here are a direct result of a reduction in potassium current
densities. However, research also supports the possibility
of non-conductive roles for potassium and other ion chan-
nels, through signaling that is regulated by proteolytic cleav-
age of channel proteins or activation of classical kinase
pathways. Thus, it is also conceivable that hERG possesses
conductance-independent functions that are as-yet not clearly
defined. Regardless, the diverse functions of the channel,
causal or not, provide evidence that hERG could be targeted
in therapies for many non-cardiac diseases, provided that the
potential cardiac liabilities can be safely managed.
We thank the colleagues in Min LI’s laboratory for valuable
discussions, and Alison NEAL for editorial assistance. This
work is supported by grants to Min LI from the National
Institutes of Health (GM078579, MH084691) and Maryland
Stem Cell Research Foundation (2010-MSCRFE-0164-00).
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