hERG is a gene that codes for a protein known as Kv11.1, the alpha subunit of a
potassium ion channel. This ion channel is best known for its contribution to
the electrical activity of the heart that coordinates the heart's beating.
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. 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.
Function hERG forms the major portion of one of
the ion channel proteins) that conducts potassium ions out of the muscle cells
of the heart, and this current is critical in correctly timing the return
to the resting state of the cell membrane during the cardiac action
potential. Sometimes, when referring to the pharmacological effects of drugs,
the terms "hERG channels" and IKr are used interchangeably, but, in the
technical sense, "hERG channels" can be made only by scientists in the
laboratory; in formal terms, the naturally occurring channels in the body
that include hERG are referred to by the name of the electrical current that has
been measured in that cell type, so, for example, in the heart, the correct name
is IKr. This difference in nomenclature becomes clearer in the controversy as to
whether the channels conducting IKr include other subunits or whether the
channels include a mixture of different types of hERG, but, when the
originally-discovered form of hERG is experimentally transferred into cells
that previously lacked hERG, a potassium ion channel is formed, and this channel
has many signature features of the cardiac 'rapid' delayed rectifier
current, including IKr's inward rectification that results in the
channel producing a 'paradoxical resurgent current' in response to
repolarization of the membrane. Structure
A detailed atomic structure for hERG based on X-ray crystallography is not
yet available, so structural details for hERG are based on analogy with other ion
channels, computer models, pharmacology, and mutagenesis studies. In the
laboratory the heterologously expressed hERG potassium channel comprises 4
identical alpha subunits, which form the channel's pore through the plasma
membrane. Each hERG subunit consists of 6 transmembrane alpha helices, numbered
S1-S6, a pore helix situated between S5 and S6, and cytoplasmically located N-
and C-termini. The S4 helix contains a positively charged arginine or lysine
amino acid residue at every 3rd position and is thought to act as a
voltage-sensitive sensor, which allows the channel to respond to voltage
changes by changing conformations between conducting and non-conducting
states. Between the S5 and S6 helices, there is an extracellular loop and 'the
pore loop', which begins and ends extracellularly but loops into the
plasma membrane; the pore loop for each of the hERG subunits in one channel face
into the ion-conducting pore and are adjacent to the corresponding loops of
the 3 other subunits, and together they form the selectivity filter region of
the channel pore. The selectivity sequence, SVGFG, is very similar to that
contained in bacterial KcsA channels. Although a full crystal structure for
hERG is not yet available, a structure has been found for the cytoplasmic
N-terminus, which was shown to contain a PAS domain that slows the rate of
deactivation. Genetics
Loss of function mutations in this channel may lead to long QT syndrome,
while gain of function mutations may lead to short QT syndrome. Both clinical
disorders stem from ion channel dysfunction that can lead to the risk of
potentially fatal cardiac arrhythmias, due to repolarization disturbances of
the cardiac action potential. There are far more hERG mutations described for
long QT syndrome than for short QT syndrome.
Drug interactions This channel is also sensitive to drug
binding, as well as decreased extracellular potassium levels, both of
which can result in decreased channel function and drug-induced long QT
syndrome. Among the drugs that can cause QT prolongation, the more common ones
include antiarrhythmics, anti-psychotic agents, and certain antibiotics.
Although there exist other potential targets for cardiac adverse effects, the
vast majority of drugs associated with acquired QT prolongation are known to
interact with the hERG potassium channel. One of the main reasons for
this phenomenon is the larger inner vestibule of the hERG channel, thus
providing more space for many different drug classes to bind and block this
potassium channel. Due to the awareness of the potential
danger of such QT drugs the regulatory authorities issued recommendations for
the establishment of cardiac safety during preclinical drug development: ICH
S7B, The nonclinical evaluation of the potential for delayed ventricular
repolarization by human pharmaceuticals, issued as CHMP423/02, adopted by CHMP in
May 2005. Preclinical hERG studies should be accomplished in GLP
environment. Naming
The hERG gene was first named and described in a paper by Jeff Warmke and
Barry Ganetzky, then both at the University of Wisconsin–Madison. The
hERG gene is the human homolog of the Ether-à-go-go gene found in the
Drosophila fly; Ether-à-go-go was named in the 1960s by William D. Kaplan, while
at the City of Hope Hospital in Duarte, California. When flies with mutations in
the Ether-à-go-go gene are anaesthetised with ether, their legs start to shake,
like the dancing then popular at the Whisky A Go-Go nightclub in West
Hollywood, California. Interactions
HERG has been shown to interact with YWHAE.
See also Voltage-gated potassium channel
References Further reading
External links GeneReviewsNCBI/UW entry on Romano-Ward
Syndrome The HERG Association
International Conference on Harmoniozation
Drosphila flybase entry for erg Special K: Primate-specific Potassium
Channel Variant Implicated in Schizophrenia - Schizophrenia Research
Forum.