hERG

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Potassium voltage-gated channel, subfamily H (eag-related), member 2
250px PDB rendering of the N-terminal domain based on 1byw.
Available structures PDB 1byw, 1ujl
Identifiers
Symbols	KCNH2; ERG1; HERG; HERG1; Kv11.1; LQT2; SQT1
External IDs	OMIM: 152427 MGI: 1341722 HomoloGene: 201 IUPHAR: Kv11.1 GeneCards: KCNH2 Gene
Gene Ontology Molecular function • two-component sensor activity • ion channel activity • voltage-gated potassium channel activity • delayed rectifier potassium channel activity • potassium ion binding Cellular component • membrane fraction • nuclear envelope • cytoplasm • plasma membrane • voltage-gated potassium channel complex • membrane • integral to membrane Biological process • two-component signal transduction system (phosphorelay) • regulation of transcription, DNA-dependent • ion transport • potassium ion transport • muscle contraction • sensory perception of sound • regulation of heart contraction Sources: Amigo / EGO
RNA expression pattern
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More reference expression data
Orthologs
Species	Human	Mouse
Entrez	3757	16511
Ensembl	ENSG00000055118	ENSMUSG00000038319
UniProt	Q12809	Q53Z09
RefSeq (mRNA)	NM_000238	XM_981382
RefSeq (protein)	NP_000229	XP_986476
Location (UCSC)	Chr 7: 150.27 - 150.31 Mb	Chr 5: 23.83 - 23.86 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 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 an unwanted side effect, which has made hERG inhibition an important antitarget which 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.

Biological 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 seemingly interchangeably, but technically "hERG channels" can only be made by scientists in the laboratory; formally speaking, 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 cystallography 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 3^rd 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 that slows the rate of deactivation.

Genetics

Abnormalities in this channel may lead to either Long QT syndrome (LQT2) (with loss of function mutations) or Short QT syndrome (with gain of function mutations), both clinical disorders stemming from ion channel dysfunction (so-called channelopathies) that can lead to the risk potentially fatal cardiac arrhythmias (e.g., Torsades de pointes), due to repolarization disturbances of the cardiac action potential. There are far more known 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.

The name

The hERG gene was first named and described in a paper by Jeff Warmke and Barry Ganetzky, then both at the University of Wisconsin. 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, now 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.

Further reading

• Vincent GM (1998). "The molecular genetics of the long QT syndrome: genes causing fainting and sudden death". Annu. Rev. Med. 49: 263–74. doi:10.1146/annurev.med.49.1.263. PMID 9509262. 
• Ackerman MJ (1998). "The long QT syndrome: ion channel diseases of the heart". Mayo Clin. Proc. 73 (3): 250–69. doi:10.4065/73.3.250. PMID 9511785. 
• Taglialatela M, Castaldo P, Pannaccione A; et al. (1998). "Human ether-a-gogo related gene (HERG) K+ channels as pharmacological targets: present and future implications". Biochem. Pharmacol. 55 (11): 1741–6. doi:10.1016/S0006-2952(98)00002-1. PMID 9714291. CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
• Bjerregaard P, Gussak I (2005). "Short QT syndrome: mechanisms, diagnosis and treatment". Nature clinical practice. Cardiovascular medicine. 2 (2): 84–7. doi:10.1038/ncpcardio0097. PMID 16265378. 
• Gutman GA, Chandy KG, Grissmer S; et al. (2006). "International Union of Pharmacology. LIII. Nomenclature and molecular relationships of voltage-gated potassium channels". Pharmacol. Rev. 57 (4): 473–508. doi:10.1124/pr.57.4.10. PMID 16382104. CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)

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.

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