HERG
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The hERG (human Ether-a-go-go Related Gene) (KCNH2) encodes the Kv11.1 potassium ion channel responsible for the repolarizing IKr current in the cardiac action potential.
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[edit] Structure
The hERG potassium channel comprises 4 identical subunits each containing 6 transmembrane domains, numbered S1-S6, a pore helix and a slide helix. The S4 helix contains a arginine or lysine at every 3rd position and is thought to be the voltage-sensitive sensor. The pore helix linking the S5 and S6 helices form interface with the pore helices of the 3 other subunits to form the selectivity filter and pore of the channel. The selectivity sequence, SVGFG, is very similar to that of KcsA channels
[edit] 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 potentially fatal cardiac arrhythmia, due to repolarisation disturbances of the cardiac action potential.[1][2]
[edit] 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 the 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).[3]
Although there exist other potential targets for cardiac adverse effects, the vast majority of drugs associated with acquired QT prolongation is 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.[4]
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.
[edit] The name
The hERG gene is the human homolog of the Ether-a-go-go gene found in the Drosophila fly and named in the 1960s by William D. Kaplan, now at the City of Hope Hospital in Duarte, California. When flies with mutations in this 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.
[edit] References
- ^ 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:. 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:. PMID 11854117.
- ^ Sanguinetti MC, Tristani-Firouzi M (2006). "hERG potassium channels and cardiac arrhythmia". Nature 440 (7083): 463–9. doi:. 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:. PMID 12839862.
[edit] 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:. PMID 9509262.
- Ackerman MJ (1998). "The long QT syndrome: ion channel diseases of the heart.". Mayo Clin. Proc. 73 (3): 250–69. 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:. PMID 9714291.
- Bjerregaard P, Gussak I (2005). "Short QT syndrome: mechanisms, diagnosis and treatment.". Nature clinical practice. Cardiovascular medicine 2 (2): 84–7. doi:. 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:. PMID 16382104.
[edit] See also
[edit] External links
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