ヒト遅延整流性カリウムイオンチャネル遺伝子

関: human ether-a-go-go-related gene

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2017/04/08 23:51:45」(JST)

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hERG (human Ether-a-go-go Related Gene) とは、心筋活動電位の再分極を担う、カリウムイオンチャンネルK_v11.1をコードする遺伝子である。

構造

hERGカリウムチャンネルは、それぞれ６個（S1－S6）の膜貫通領域を含む４つの同一のサブユニットから構成されている。S4ヘリックスはアルギニンもしくはライシンを3ヶ所ごとに持ち、電位センサーとして作用すると考えられている。S5ヘリックスとS6ヘリックスを連結しているポアヘリックスは、その他の3つのサブユニットとの結合部分となり、イオンチャンネルの細孔を形成して選択透過性を発現している。選択透過の過程（SVGFG）はKcsAチャンネルの動作と非常に類似している。

遺伝学

このイオンチャンネルの異常は、機能喪失型変異によりQT延長症候群（LQTS）を、機能獲得型変異によりQT短縮症候群を引き起こしうる。心筋活動電位の再分極の乱れから生じるQT延長、短縮はともに致命的な不整脈の原因となる。^[1]^[2]

薬物相互作用

このイオンチャンネルは、薬物との結合や細胞外のカリウムレベルの低下に対して敏感である。どちらの場合も結果としてチャンネルの機能低下やQT延長症候群を起こす。ある種の抗不整脈薬（特にIa群とIII群）、抗精神病薬、キノロン系とマクロライド系抗生物質においてQT延長の副作用が見られることがある。 ^[3]

心臓に対する副作用を起こす機構は他にも存在するが、多くのQT延長を起こす例において薬物とhERGカリウムイオンチャンネルとの間に相互作用があることが知られている。この現象の主な原因はｈERGチャンネルの前庭部分が大きいことによる。そのため、より多くの異なる種類の薬物がカリウムチャンネルと結合し、チャンネルをブロックする余地がある。 ^[4]

このような薬物によるQT異常の危険性が認知されたため、行政当局は臨床前開発における心疾患安全性の確立に対する勧告を出した（ICH S7B、心室再分極遅延（QT間隔遅延）の薬学的臨床前評価）。この勧告はCHMP（欧州医薬品審査庁の医薬品委員会）により2005年5月により承認され、CHMP/ICH/423/02として公布された。臨床前のhERG研究はGLP環境により行われなければならない。

逆に、新薬開発の観点からは、探索の初期段階で候補化合物とhERGカリウムイオンチャンネルとの結合の強さを試験し、心疾患の危険性をある程度回避することが期待できる。これにより開発費用と時間を節約することができるため、2008年現在、分子構造と結合の強さとの間の相関関係の研究が盛んに行われている。hERGカリウムイオンチャンネルとの結合しやすい化合物には以下の特徴が共通して見られる。^[5]

塩基性アミンを持つ（陽イオン化しやすい。pK_a >7.3）。
疎水性/親油性部分構造（ClogP >3.7)。
陰イオン化できる置換基を持たない。
水素結合を受け入れる酸素原子を持たない。

名称の由来

hERGは、1960年代、William D. Kaplan （現在、カリフォルニア州ドアルテにあるCity of Hope Hospitaに在籍）により、ショウジョウバエにおいて見出されたether-a-go-go遺伝子のヒトホモログであることからhERG遺伝子と呼ばれる。この遺伝子に変異が生じたショウジョウバエをエーテルで麻酔すると、ダンスするように脚を震えさせたことから、カリフォルニア州ウェスト・ハリウッドのナイトクラブ「ウィスキー・ア・ゴーゴー」において当時人気であったダンスにちなんでether-a-go-go遺伝子と命名された。

脚注

^ Sanguinetti MC, Jiang C, Curran ME, Keating MT (1995). “A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel”. Cell 81 (2): 299–307. doi:10.1016/0092-8674(95)90340-2. PMID 7736582.
^ Moss AJ, Zareba W, Kaufman ES, Gartman E, Peterson DR, Benhorin J, Towbin JA, Keating MT, Priori SG, Schwartz PJ, Vincent GM, Robinson JL, Andrews ML, Feng C, Hall WJ, Medina A, Zhang L, Wang Z (2002). “Increased risk of arrhythmic events in long-QT syndrome with mutations in the pore region of the human ether-a-go-go-related gene potassium channel”. Circulation 105 (7): 794–9. doi:10.1161/hc0702.105124. PMID 11854117.
^ Sanguinetti MC, Tristani-Firouzi M (2006). “hERG potassium channels and cardiac arrhythmia”. Nature 440 (7083): 463–9. doi:10.1038/nature04710. PMID 16554806.
^ Milnes JT, Crociani O, Arcangeli A, Hancox JC, Witchel HJ (2003). “Blockade of HERG potassium currents by fluvoxamine: incomplete attenuation by S6 mutations at F656 or Y652”. Br J Pharmacol 139 (5): 887–98. doi:10.1038/sj.bjp.0705335. PMID 12839862.
^ Kerns, E. H.; Di, L. (2008). Drug-like properties: concepts, structure design and methods from ADME to toxicity optimization. Burlington, Massachusetts: Academic press. pp. 212. ISBN 978-01236-9520-8.

参考文献

"The molecular genetics of the long QT syndrome: genes causing fainting and sudden death" Annu. Rev. Med., 49, pp. 263–74 (1998).
"The long QT syndrome: ion channel diseases of the heart" Mayo Clin. Proc., 73(3), pp. 250–69 (1998).
Taglialatela M, Castaldo P, Pannaccione A, et al. "Human ether-a-gogo related gene (HERG) K+ channels as pharmacological targets: present and future implications" Biochem. Pharmacol., 55(11), pp. 1741–6 (1998) .
Bjerregaard P, Gussak I "Short QT syndrome: mechanisms, diagnosis and treatment" Nature clinical practice. Cardiovascular medicine, 2(2), pp. 84–7 (2005).
Gutman GA, Chandy KG, Grissmer S, et al. "International Union of Pharmacology. LIII. Nomenclature and molecular relationships of voltage-gated potassium channels" Pharmacol. Rev., 57(4), pp. 473–508 (2006).

外部リンク

The HERG Association
Drosphila flybase entry for erg
HUGO Gene Nomenclature Committee

この項目は、薬学に関連した書きかけの項目です。この項目を加筆・訂正などしてくださる協力者を求めています（プロジェクト:薬学／Portal:医学と医療）。

この項目は、医学に関連した書きかけの項目です。この項目を加筆・訂正などしてくださる協力者を求めています（プロジェクト:医学／Portal:医学と医療）。

wiki en

[Wiki en表示]

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,^[4] 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.^[5] hERG has also been associated with modulating the functions of some cells of the nervous system^[6] and with establishing and maintaining cancer-like features in leukemic cells.^[7]

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.^[5] 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^[8]) or whether the channels include a mixture of different types (isoforms) of hERG,^[9] but, when the originally-discovered form of hERG^[10] 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),^[11]^[12]^[13] including I_Kr's inward rectification that results in the channel producing a 'paradoxical resurgent current' in response to repolarization of the membrane.^[14]

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.^[5] 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.^[15]

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.^[11]^[16] There are far more hERG mutations described for long QT syndrome than for short QT syndrome.^[4]

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).^[17]

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.^[18]

Drug Development Considerations

Due to the documented potential of QT interval prolonging drugs, the United States Food and Drug Administration issued recommendations for the establishment of a cardiac safety profile during pre-clinical drug development: ICH S7B.^[19] 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.^[20] 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.^[21]

References

^ "Drugs that physically interact with Potassium voltage-gated channel subfamily H member 2 view/edit references on wikidata".
^ "Human PubMed Reference:".
^ "Mouse PubMed Reference:".
^ ^a ^b Hedley PL, Jørgensen P, Schlamowitz S, Wangari R, Moolman-Smook J, Brink PA, Kanters JK, Corfield VA, Christiansen M (2009). "The genetic basis of long QT and short QT syndromes: a mutation update". Hum. Mutat. 30 (11): 1486–511. doi:10.1002/humu.21106. PMID 19862833.
^ ^a ^b ^c Sanguinetti MC, Tristani-Firouzi M (March 2006). "hERG potassium channels and cardiac arrhythmia". Nature. 440 (7083): 463–9. doi:10.1038/nature04710. PMID 16554806.
^ Chiesa N, Rosati B, Arcangeli A, Olivotto M, Wanke E (June 1997). "A novel role for HERG K+ channels: spike-frequency adaptation". J. Physiol. (Lond.). 501 ( Pt 2) (2): 313–8. doi:10.1111/j.1469-7793.1997.313bn.x. PMC 1159479. PMID 9192303. Overholt JL, Ficker E, Yang T, Shams H, Bright GR, Prabhakar NR (2000). "Chemosensing at the carotid body. Involvement of a HERG-like potassium current in glomus cells". Adv. Exp. Med. Biol. 475: 241–8. doi:10.1007/0-306-46825-5_22. PMID 10849664.
^ Arcangeli A (2005). "Expression and role of hERG channels in cancer cells". Novartis Found. Symp. 266: 225–32; discussion 232–4. doi:10.1002/047002142X.ch17. PMID 16050271.
^ Weerapura M, Nattel S, Chartier D, Caballero R, Hébert TE (April 2002). "A comparison of currents carried by HERG, with and without coexpression of MiRP1, and the native rapid delayed rectifier current. Is MiRP1 the missing link?". J. Physiol. (Lond.). 540 (Pt 1): 15–27. doi:10.1113/jphysiol.2001.013296. PMC 2290231. PMID 11927665. Archived from the original on October 18, 2014. Abbott GW, Goldstein SA (March 2002). "Disease-associated mutations in KCNE potassium channel subunits (MiRPs) reveal promiscuous disruption of multiple currents and conservation of mechanism". FASEB J. 16 (3): 390–400. doi:10.1096/fj.01-0520hyp. PMID 11874988. Abbott GW, Sesti F, Splawski I, Buck ME, Lehmann MH, Timothy KW, Keating MT, Goldstein SA (April 1999). "MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia". Cell. 97 (2): 175–87. doi:10.1016/S0092-8674(00)80728-X. PMID 10219239.
^ Jones EM, Roti Roti EC, Wang J, Delfosse SA, Robertson GA (October 2004). "Cardiac IKr channels minimally comprise hERG 1a and 1b subunits". J. Biol. Chem. 279 (43): 44690–4. doi:10.1074/jbc.M408344200. PMID 15304481. Robertson GA, Jones EM, Wang J (2005). "Gating and assembly of heteromeric hERG1a/1b channels underlying I(Kr) in the heart". Novartis Found. Symp. 266: 4–15; discussion 15–8, 44–5. doi:10.1002/047002142X.ch2. PMID 16050259.
^ Warmke JW, Ganetzky B (April 1994). "A family of potassium channel genes related to eag in Drosophila and mammals". Proc. Natl. Acad. Sci. U.S.A. 91 (8): 3438–42. doi:10.1073/pnas.91.8.3438. PMC 43592. PMID 8159766. Trudeau MC, Warmke JW, Ganetzky B, Robertson GA (July 1995). "HERG, a human inward rectifier in the voltage-gated potassium channel family". Science. 269 (5220): 92–5. doi:10.1126/science.7604285. PMID 7604285. Sanguinetti MC, Jiang C, Curran ME, Keating MT (April 1995). "A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel". Cell. 81 (2): 299–307. doi:10.1016/0092-8674(95)90340-2. PMID 7736582.
^ ^a ^b Sanguinetti MC, Jiang C, Curran ME, Keating MT (1995). "A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel". Cell. 81 (2): 299–307. doi:10.1016/0092-8674(95)90340-2. PMID 7736582.
^ Trudeau MC, Warmke JW, Ganetzky B, Robertson GA (July 1995). "HERG, a human inward rectifier in the voltage-gated potassium channel family". Science. 269 (5220): 92–5. doi:10.1126/science.7604285. PMID 7604285.
^ Robertson GA, Jones EM, Wang J (2005). "Gating and assembly of heteromeric hERG1a/1b channels underlying I(Kr) in the heart". Novartis Found. Symp. 266: 4–15; discussion 15–8, 44–5. doi:10.1002/047002142X.ch2. PMID 16050259.
^ Robertson GA (March 2000). "LQT2 : amplitude reduction and loss of selectivity in the tail that wags the HERG channel". Circ. Res. 86 (5): 492–3. doi:10.1161/01.res.86.5.492. PMID 10720408.
^ Morais Cabral JH, Lee A, Cohen SL, Chait BT, Li M, Mackinnon R (November 1998). "Crystal structure and functional analysis of the HERG potassium channel N terminus: a eukaryotic PAS domain". Cell. 95 (5): 649–55. doi:10.1016/S0092-8674(00)81635-9. PMID 9845367.
^ Moss AJ, Zareba W, Kaufman ES, Gartman E, Peterson DR, Benhorin J, Towbin JA, Keating MT, Priori SG, Schwartz PJ, Vincent GM, Robinson JL, Andrews ML, Feng C, Hall WJ, Medina A, Zhang L, Wang Z (2002). "Increased risk of arrhythmic events in long-QT syndrome with mutations in the pore region of the human ether-a-go-go-related gene potassium channel". Circulation. 105 (7): 794–9. doi:10.1161/hc0702.105124. PMID 11854117.
^ Sanguinetti MC, Tristani-Firouzi M (2006). "hERG potassium channels and cardiac arrhythmia". Nature. 440 (7083): 463–9. doi:10.1038/nature04710. PMID 16554806.
^ Milnes JT, Crociani O, Arcangeli A, Hancox JC, Witchel HJ (2003). "Blockade of HERG potassium currents by fluvoxamine: incomplete attenuation by S6 mutations at F656 or Y652". Br. J. Pharmacol. 139 (5): 887–98. doi:10.1038/sj.bjp.0705335. PMC 1573929. PMID 12839862.
^ https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm074963.pdf
^ Warmke JW, Ganetzky B (April 1994). "A family of potassium channel genes related to eag in Drosophila and mammals". Proc. Natl. Acad. Sci. U.S.A. 91 (8): 3438–42. doi:10.1073/pnas.91.8.3438. PMC 43592. PMID 8159766.
^ Kagan A, Melman YF, Krumerman A, McDonald TV (Apr 2002). "14-3-3 amplifies and prolongs adrenergic stimulation of HERG K+ channel activity". EMBO J. 21 (8): 1889–98. doi:10.1093/emboj/21.8.1889. PMC 125975. PMID 11953308.

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.

UpToDate Contents

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1. 先天性および後天性ＱＴ延長症候群の遺伝学 genetics of congenital and acquired long qt syndrome
2. 後天性ＱＴ延長症候群 acquired long qt syndrome
3. 先天性QT延長症候群の臨床的特徴 clinical features of congenital long qt syndrome
4. 明らかな器質的心疾患のない患者における突然の心停止 sudden cardiac arrest in the absence of apparent structural heart disease
5. 成人における高カリウム血症の臨床症状 clinical manifestations of hyperkalemia in adults

English Journal

Toxin modulators and blockers of hERG K(+) channels.

Jiménez-Vargas JM, Restano-Cassulini R, Possani LD.SourceDepartment of Molecular Medicine and Bioprocesses, Institute of Biotechnology, National Autonomous University of Mexico, Av. Universidad 2001, P.O. Box 501-3, Cuernavaca 62210, Mexico.
Toxicon : official journal of the International Society on Toxinology.Toxicon.2012 Sep 15;60(4):492-501. Epub 2012 Apr 5.
The K(+) channel encoded by the Ether-á-go-go-Related Gene (ERG) is expressed in different tissues of different animal species. There are at least three subtypes of this channel, being the sub-type 1 (ERG1) crucial in the repolarization phase of the cardiac action potential. Mutations in this gene
PMID 22497787

Synthesis and In Vitro Antibacterial Activity of Novel 3-Azabicyclo[3.3.0]octanyl Oxazolidinones.

Bhattarai D, Lee SH, Seo SH, Nam G, Kang SB, Pae AN, Kim EE, Oh T, Cho SN, Keum G.SourceCenter for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology, Hwarangro 14-gil 5 Seongbuk-gu, Seoul 136-791, Korea Department of Biomolecular Science, University of Science and Technology, Gajungro 217, Youseong-gu, Daejeon 305-350, Korea Department of Microbiology and the Brain Korea 21 Project for the Medical Sciences, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.
Chemical biology & drug design.Chem Biol Drug Des.2012 Sep;80(3):388-97. doi: 10.1111/j.1747-0285.2012.01404.x. Epub 2012 Jun 27.
We synthesized a series of oxazolidinone-type antibacterials in which morpholine C-ring of linezolid has been modified by substituted 3-azabicyclo[3.3.0]octanyl rings. Acetamide or 1,2,3-triazole heterocycle was used as C-5 side chain of oxazolidinone. The resulting series of compounds was then scre
PMID 22553981

Japanese Journal

Effects of an hERG Activator, ICA-105574, on Electrophysiological Properties of Canine Hearts

Asayama Mahoko,Kurokawa Junko,Shirakawa Kiyoshi [他]
Journal of pharmacological sciences 121(1), 1-8, 2013-01
NAID 40019554426

Effects of the Antitussive Drug Cloperastine on Ventricular Repolarization in Halothane-Anesthetized Guinea Pigs

Takahara Akira,Fujiwara Kaori,Ohtsuki Atsushi,Oka Takayuki,Namekata Iyuki,Tanaka Hikaru
Journal of Pharmacological Sciences 2012(0), 165, 2012
… The chemical structure of cloperastine is quite similar to that of the antihistamine drug diphenhydramine, which is reported to inhibit hERG K+ … To analyze its proarrhythmic potential, we compared effects of cloperastine and diphenhydramine on the hERG K+ … Cloperastine inhibited the hERG K+ …
NAID 130001888865

Blockade of K+ and Ca2+ Channels by Azole Antifungal Agents in Neonatal Rat Ventricular Myocytes

Sung Dong-Jun,Kim Jae-Gon,Won Kyung Jong,Kim Bokyung,Shin Ho Chul,Park Jae-Yong,Bae Young Min
Biological and Pharmaceutical Bulletin 35(9), 1469-1475, 2012
… Although composite functions of ion channels in cardiomyocytes contribute to the shaping of action potentials, information on the effects of azole antifungal agents on ion currents, except human-ether-a-go-go-related gene (HERG) K+ currents, is largely lacking. …
NAID 130001872067

「human ether-a-go-go-related gene」

KCNH2
Available structures
PDB	Ortholog search: PDBe RCSB
List of PDB id codes
	1BYW, 1UJL, 2L0W, 2L1M, 2L4R, 2LE7, 4HP9, 4HQA, 2N7G
Identifiers
Aliases	KCNH2, ERG-1, ERG1, H-ERG, HERG, HERG1, Kv11.1, LQT2, SQT1, potassium voltage-gated channel subfamily H member 2
External IDs	MGI: 1341722 HomoloGene: 201 GeneCards: KCNH2
Targeted by Drug
	rottlerin, disopyramide, dofetilide, astemizole, E4031, ibutilide, terfenadine
Gene ontology
Molecular function	• potassium channel activity; • protein homodimerization activity; • scaffold protein binding; • voltage-gated potassium channel activity involved in cardiac muscle cell action potential repolarization; • C3HC4-type RING finger domain binding; • voltage-gated ion channel activity; • ion channel activity; • protein binding; • identical protein binding; • voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization; • voltage-gated potassium channel activity; • phosphorelay sensor kinase activity; • inward rectifier potassium channel activity; • ubiquitin protein ligase binding; • delayed rectifier potassium channel activity;
Cellular component	• integral component of membrane; • membrane; • voltage-gated potassium channel complex; • plasma membrane; • cell surface; • perinuclear region of cytoplasm;
Biological process	• membrane depolarization during action potential; • cardiac muscle contraction; • potassium ion export; • signal transduction by protein phosphorylation; • regulation of membrane potential; • regulation of ion transmembrane transport; • ventricular cardiac muscle cell action potential; • ion transport; • potassium ion export across plasma membrane; • potassium ion transport; • cellular response to drug; • membrane repolarization during action potential; • cardiac conduction; • potassium ion homeostasis; • negative regulation of potassium ion export; • regulation of heart rate by hormone; • transmembrane transport; • potassium ion transmembrane transport; • positive regulation of potassium ion transmembrane transport; • transport; • phosphorelay signal transduction system; • regulation of membrane repolarization; • negative regulation of potassium ion transmembrane transport; • membrane repolarization during cardiac muscle cell action potential; • regulation of heart rate by cardiac conduction; • regulation of potassium ion transmembrane transport; • regulation of ventricular cardiac muscle cell membrane repolarization; • membrane repolarization during ventricular cardiac muscle cell action potential;
	Sources:Amigo / QuickGO
RNA expression pattern
	; ; ; ;
	More reference expression data
Orthologs
	3757
	16511
	ENSG00000055118
	ENSMUSG00000038319
	Q12809
	O35219
	NM_000238; NM_001204798; NM_172056; NM_172057
	NM_001294162; NM_013569
	NP_000229; NP_001191727; NP_742053; NP_742054
	NP_001281091.1; NP_001281091; NP_038597
	Wikidata
View/Edit Human	View/Edit Mouse

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ヒト遅延整流性カリウムイオンチャネル遺伝子

関: HERG

「ヒト遅延整流性カリウムイオンチャネル遺伝子」

　　[★]

英: human ether-a-go-go-related gene、HERG

[Sanguinetti__1995-1] Sanguinetti MC, Jiang C, Curran ME, Keating MT (1995). “A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel”. Cell 81 (2): 299–307. doi:10.1016/0092-8674(95)90340-2. PMID 7736582.

[Moss-2] Moss AJ, Zareba W, Kaufman ES, Gartman E, Peterson DR, Benhorin J, Towbin JA, Keating MT, Priori SG, Schwartz PJ, Vincent GM, Robinson JL, Andrews ML, Feng C, Hall WJ, Medina A, Zhang L, Wang Z (2002). “Increased risk of arrhythmic events in long-QT syndrome with mutations in the pore region of the human ether-a-go-go-related gene potassium channel”. Circulation 105 (7): 794–9. doi:10.1161/hc0702.105124. PMID 11854117.

[Sanguinetti-3] Sanguinetti MC, Tristani-Firouzi M (2006). “hERG potassium channels and cardiac arrhythmia”. Nature 440 (7083): 463–9. doi:10.1038/nature04710. PMID 16554806.

[Milnes-4] Milnes JT, Crociani O, Arcangeli A, Hancox JC, Witchel HJ (2003). “Blockade of HERG potassium currents by fluvoxamine: incomplete attenuation by S6 mutations at F656 or Y652”. Br J Pharmacol 139 (5): 887–98. doi:10.1038/sj.bjp.0705335. PMID 12839862.

[5] Kerns, E. H.; Di, L. (2008). Drug-like properties: concepts, structure design and methods from ADME to toxicity optimization. Burlington, Massachusetts: Academic press. pp. 212. ISBN 978-01236-9520-8.

[1] "Drugs that physically interact with Potassium voltage-gated channel subfamily H member 2 view/edit references on wikidata".

[2] "Human PubMed Reference:".

[3] "Mouse PubMed Reference:".

[Hedley-4] Hedley PL, Jørgensen P, Schlamowitz S, Wangari R, Moolman-Smook J, Brink PA, Kanters JK, Corfield VA, Christiansen M (2009). "The genetic basis of long QT and short QT syndromes: a mutation update". Hum. Mutat. 30 (11): 1486–511. doi:10.1002/humu.21106. PMID 19862833.

[Sanguinetti_MC.2C_Tristani-Firouzi_M_2006_463.E2.80.939-5] Sanguinetti MC, Tristani-Firouzi M (March 2006). "hERG potassium channels and cardiac arrhythmia". Nature. 440 (7083): 463–9. doi:10.1038/nature04710. PMID 16554806.

[6] Chiesa N, Rosati B, Arcangeli A, Olivotto M, Wanke E (June 1997). "A novel role for HERG K+ channels: spike-frequency adaptation". J. Physiol. (Lond.). 501 ( Pt 2) (2): 313–8. doi:10.1111/j.1469-7793.1997.313bn.x. PMC 1159479. PMID 9192303. Overholt JL, Ficker E, Yang T, Shams H, Bright GR, Prabhakar NR (2000). "Chemosensing at the carotid body. Involvement of a HERG-like potassium current in glomus cells". Adv. Exp. Med. Biol. 475: 241–8. doi:10.1007/0-306-46825-5_22. PMID 10849664.

[7] Arcangeli A (2005). "Expression and role of hERG channels in cancer cells". Novartis Found. Symp. 266: 225–32; discussion 232–4. doi:10.1002/047002142X.ch17. PMID 16050271.

[8] Weerapura M, Nattel S, Chartier D, Caballero R, Hébert TE (April 2002). "A comparison of currents carried by HERG, with and without coexpression of MiRP1, and the native rapid delayed rectifier current. Is MiRP1 the missing link?". J. Physiol. (Lond.). 540 (Pt 1): 15–27. doi:10.1113/jphysiol.2001.013296. PMC 2290231. PMID 11927665. Archived from the original on October 18, 2014. Abbott GW, Goldstein SA (March 2002). "Disease-associated mutations in KCNE potassium channel subunits (MiRPs) reveal promiscuous disruption of multiple currents and conservation of mechanism". FASEB J. 16 (3): 390–400. doi:10.1096/fj.01-0520hyp. PMID 11874988. Abbott GW, Sesti F, Splawski I, Buck ME, Lehmann MH, Timothy KW, Keating MT, Goldstein SA (April 1999). "MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia". Cell. 97 (2): 175–87. doi:10.1016/S0092-8674(00)80728-X. PMID 10219239.

[9] Jones EM, Roti Roti EC, Wang J, Delfosse SA, Robertson GA (October 2004). "Cardiac IKr channels minimally comprise hERG 1a and 1b subunits". J. Biol. Chem. 279 (43): 44690–4. doi:10.1074/jbc.M408344200. PMID 15304481. Robertson GA, Jones EM, Wang J (2005). "Gating and assembly of heteromeric hERG1a/1b channels underlying I(Kr) in the heart". Novartis Found. Symp. 266: 4–15; discussion 15–8, 44–5. doi:10.1002/047002142X.ch2. PMID 16050259.

[10] Warmke JW, Ganetzky B (April 1994). "A family of potassium channel genes related to eag in Drosophila and mammals". Proc. Natl. Acad. Sci. U.S.A. 91 (8): 3438–42. doi:10.1073/pnas.91.8.3438. PMC 43592. PMID 8159766. Trudeau MC, Warmke JW, Ganetzky B, Robertson GA (July 1995). "HERG, a human inward rectifier in the voltage-gated potassium channel family". Science. 269 (5220): 92–5. doi:10.1126/science.7604285. PMID 7604285. Sanguinetti MC, Jiang C, Curran ME, Keating MT (April 1995). "A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel". Cell. 81 (2): 299–307. doi:10.1016/0092-8674(95)90340-2. PMID 7736582.

[Sanguinetti__1995-11] Sanguinetti MC, Jiang C, Curran ME, Keating MT (1995). "A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel". Cell. 81 (2): 299–307. doi:10.1016/0092-8674(95)90340-2. PMID 7736582.

[12] Trudeau MC, Warmke JW, Ganetzky B, Robertson GA (July 1995). "HERG, a human inward rectifier in the voltage-gated potassium channel family". Science. 269 (5220): 92–5. doi:10.1126/science.7604285. PMID 7604285.

[13] Robertson GA, Jones EM, Wang J (2005). "Gating and assembly of heteromeric hERG1a/1b channels underlying I(Kr) in the heart". Novartis Found. Symp. 266: 4–15; discussion 15–8, 44–5. doi:10.1002/047002142X.ch2. PMID 16050259.

[14] Robertson GA (March 2000). "LQT2 : amplitude reduction and loss of selectivity in the tail that wags the HERG channel". Circ. Res. 86 (5): 492–3. doi:10.1161/01.res.86.5.492. PMID 10720408.

[pmid9845367-15] Morais Cabral JH, Lee A, Cohen SL, Chait BT, Li M, Mackinnon R (November 1998). "Crystal structure and functional analysis of the HERG potassium channel N terminus: a eukaryotic PAS domain". Cell. 95 (5): 649–55. doi:10.1016/S0092-8674(00)81635-9. PMID 9845367.

[Moss-16] Moss AJ, Zareba W, Kaufman ES, Gartman E, Peterson DR, Benhorin J, Towbin JA, Keating MT, Priori SG, Schwartz PJ, Vincent GM, Robinson JL, Andrews ML, Feng C, Hall WJ, Medina A, Zhang L, Wang Z (2002). "Increased risk of arrhythmic events in long-QT syndrome with mutations in the pore region of the human ether-a-go-go-related gene potassium channel". Circulation. 105 (7): 794–9. doi:10.1161/hc0702.105124. PMID 11854117.

[Sanguinetti-17] Sanguinetti MC, Tristani-Firouzi M (2006). "hERG potassium channels and cardiac arrhythmia". Nature. 440 (7083): 463–9. doi:10.1038/nature04710. PMID 16554806.

[Milnes-18] Milnes JT, Crociani O, Arcangeli A, Hancox JC, Witchel HJ (2003). "Blockade of HERG potassium currents by fluvoxamine: incomplete attenuation by S6 mutations at F656 or Y652". Br. J. Pharmacol. 139 (5): 887–98. doi:10.1038/sj.bjp.0705335. PMC 1573929. PMID 12839862.

[19] ttps://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm074963.pdf

[20] Warmke JW, Ganetzky B (April 1994). "A family of potassium channel genes related to eag in Drosophila and mammals". Proc. Natl. Acad. Sci. U.S.A. 91 (8): 3438–42. doi:10.1073/pnas.91.8.3438. PMC 43592. PMID 8159766.

[pmid11953308-21] Kagan A, Melman YF, Krumerman A, McDonald TV (Apr 2002). "14-3-3 amplifies and prolongs adrenergic stimulation of HERG K+ channel activity". EMBO J. 21 (8): 1889–98. doi:10.1093/emboj/21.8.1889. PMC 125975. PMID 11953308.

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HERG