hERG

Potassium channel, voltage gated eag related subfamily H, member 2
PDB rendering of the N-terminal domain based on 1byw. This domain is just a very small piece of the total channel.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1BYW, 1UJL, 2L0W, 2L1M, 2L4R, 2LE7, 4HP9, 4HQA
Identifiers
Symbols	KCNH2 ; ERG-1; ERG1; H-ERG; HERG; HERG1; Kv11.1; LQT2; SQT1
External IDs	OMIM: 152427 MGI: 1341722 HomoloGene: 201 IUPHAR: 572 ChEMBL: 240 GeneCards: KCNH2 Gene
Gene ontology Molecular function • phosphorelay sensor kinase activity • inward rectifier potassium channel activity • voltage-gated potassium channel activity • delayed rectifier potassium channel activity • protein binding • ubiquitin protein ligase binding • identical protein binding • protein homodimerization activity • C3HC4-type RING finger domain binding • voltage-gated potassium channel activity involved in cardiac muscle cell action potential repolarization • scaffold protein binding • voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization Cellular component • nuclear envelope • plasma membrane • integral component of plasma membrane • voltage-gated potassium channel complex • cell surface • perinuclear region of cytoplasm Biological process • phosphorelay signal transduction system • regulation of heart rate by hormone • synaptic transmission • signal transduction by protein phosphorylation • cellular response to drug • regulation of membrane potential • potassium ion homeostasis • cardiac muscle contraction • regulation of membrane repolarization • regulation of ventricular cardiac muscle cell membrane repolarization • potassium ion export • potassium ion transmembrane transport • ventricular cardiac muscle cell action potential • membrane depolarization during action potential • membrane repolarization during action potential • membrane repolarization during cardiac muscle cell action potential • regulation of heart rate by cardiac conduction • potassium ion export across plasma membrane • regulation of potassium ion transmembrane transport • negative regulation of potassium ion transmembrane transport • positive regulation of potassium ion transmembrane transport • negative regulation of potassium ion export Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	3757	16511
Ensembl	ENSG00000055118	ENSMUSG00000038319
UniProt	Q12809	O35219
RefSeq (mRNA)	NM_000238	NM_001294162
RefSeq (protein)	NP_000229	NP_001281091
Location (UCSC)	Chr 7: 150.94 – 150.98 Mb	Chr 5: 24.32 – 24.35 Mb
PubMed search	[1]	[2]

hERG (the human Ether-à-go-go-Related Gene) is a gene (KCNH2) that codes for a protein known as K_v11.1, the alpha subunit of a potassium ion channel. This ion channel (sometimes simply denoted as 'hERG') is best known for its contribution to the electrical activity of the heart that coordinates the heart's beating (i.e., the hERG channel mediates the repolarizing I_Kr 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. 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 (the 'rapid' delayed rectifier current (I_Kr)) that conducts potassium (K⁺) ions out of the muscle cells of the heart (cardiac myocytes), and this current is critical in correctly timing the return to the resting state (repolarization) of the cell membrane during the cardiac action potential. Sometimes, when referring to the pharmacological effects of drugs, the terms "hERG channels" and I_Kr 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 I_Kr. This difference in nomenclature becomes clearer in the controversy as to whether the channels conducting I_Kr include other subunits (e.g., beta subunits) or whether the channels include a mixture of different types (isoforms) of hERG, but, when the originally-discovered form of hERG is experimentally transferred into cells that previously lacked hERG (i.e., heterologous expression), a potassium ion channel is formed, and this channel has many signature features of the cardiac 'rapid' delayed rectifier current (I_Kr), including I_Kr'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 (called 'gating'). Between the S5 and S6 helices, there is an extracellular loop (known as 'the turret') 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 (aminoacid 26-135) that slows the rate of deactivation.

Genetics

Loss of function mutations in this channel may lead to long QT syndrome (LQT2), while gain of function mutations may lead to short QT syndrome. Both clinical disorders stem from ion channel dysfunction (so-called channelopathies) that can lead to the risk of potentially fatal cardiac arrhythmias (e.g., torsades de pointes), 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 (acquired) long QT syndrome. Among the drugs that can cause QT prolongation, the more common ones include antiarrhythmics (especially Class 1A and Class III), anti-psychotic agents, and certain antibiotics (including quinolones and macrolides).

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 (QT interval prolongation) by human pharmaceuticals, issued as CHMP/ICH/423/02, 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 the 14-3-3 epsilon protein, encoded by YWHAE.

See also

• Voltage-gated potassium channel

External links

• GeneReviews/NIH/NCBI/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.