erg1 potassium channel

Summary

Summary: One of three members of the ether-a-go-go (EAG) POTASSIUM CHANNELS gene family comprising ether-a-go-go (eag), eag-like (elk) and eag-related (erg) subfamilies. Ether-a-go-go-related gene 1 (ERG1) also known as KCNH2, encodes the pore-forming subunit of a rapidly activating-delayed rectifier potassium channel that plays an essential role in the final repolarization of ventricular action potential. Loss-of-function mutations in human hERG1 is associated with life-threatening ARRHYTHMIA.

Top Publications

  1. Wang J, Myers C, Robertson G. Dynamic control of deactivation gating by a soluble amino-terminal domain in HERG K(+) channels. J Gen Physiol. 2000;115:749-58 pubmed
    ..We propose that the four amino-terminal deactivation subdomains of the tetrameric channel interact with binding sites uncovered by channel opening to specifically stabilize the open state and thus slow channel closing. ..
  2. Vandenberg J, Perozo E, Allen T. Towards a Structural View of Drug Binding to hERG K+ Channels. Trends Pharmacol Sci. 2017;38:899-907 pubmed publisher
    ..It also suggests a way forward in our quest to understand why these channels are so promiscuous with respect to drug binding. ..
  3. Gualdani R, Cavalluzzi M, Tadini Buoninsegni F, Lentini G. Discovery of a new mexiletine-derived agonist of the hERG K+ channel. Biophys Chem. 2017;229:62-67 pubmed publisher
    ..9±1.4mV, whereas it had no effect on the voltage dependence of activation. Furthermore, MC450 slowed current inactivation and the effect of MC450 was attenuated by the inactivation-impaired double mutant G628C/S631C. ..
  4. Luo C, Wang K, Zhang H. In silico assessment of the effects of quinidine, disopyramide and E-4031 on short QT syndrome variant 1 in the human ventricles. PLoS ONE. 2017;12:e0179515 pubmed publisher
    ..This study substantiates a causal link between quinidine and QT interval prolongation in SQT1 and suggests that quinidine may be a potential pharmacological agent for treating SQT1 patients. ..
  5. Emmerich J, van Koppen C, Burkhart J, Hu Q, Siebenbürger L, Boerger C, et al. Lead Optimization Generates CYP11B1 Inhibitors of Pyridylmethyl Isoxazole Type with Improved Pharmacological Profile for the Treatment of Cushing's Disease. J Med Chem. 2017;60:5086-5098 pubmed publisher
    ..Furthermore, compound 25 inhibited rat CYP11B1 (IC50 = 2 ?M) and showed a high oral bioavailability (F = 50%) and sufficient plasma concentrations in rats, providing an excellent starting point for a proof-of-principle study. ..
  6. Wang L, He J, Xia A, Cheng M, Yang Q, Du C, et al. Toxic effects of environmental rare earth elements on delayed outward potassium channels and their mechanisms from a microscopic perspective. Chemosphere. 2017;181:690-698 pubmed publisher
    ..These different cytotoxicities of La3+, Tb3+ and Cd2+ on human resulted from the varying binding abilities of the metals to this channel protein. ..
  7. Sangoi M, Lamothe S, Guo J, Yang T, Li W, Avery E, et al. ?-Arrestin-Mediated Regulation of the Human Ether-a-go-go-Related Gene Potassium Channel. Mol Pharmacol. 2017;92:162-174 pubmed publisher
    ..These findings provide novel insight into hERG trafficking and regulation. ..
  8. Wu D, Zhang T, Chen Y, Huang Y, Geng H, Yu Y, et al. Discovery and Optimization of Chromeno[2,3-c]pyrrol-9(2H)-ones as Novel Selective and Orally Bioavailable Phosphodiesterase 5 Inhibitors for the Treatment of Pulmonary Arterial Hypertension. J Med Chem. 2017;60:6622-6637 pubmed publisher
  9. Rubi L, Kovar M, Zebedin Brandl E, Koenig X, Dominguez Rodriguez M, Todt H, et al. Modulation of the heart's electrical properties by the anticonvulsant drug retigabine. Toxicol Appl Pharmacol. 2017;329:309-317 pubmed publisher
    ..They are rather mediated by indirect actions at the level of the autonomic nervous system. ..

More Information

Publications24

  1. Baker J, Gardiner S, Woolard J, Fromont C, Jadhav G, Mistry S, et al. Novel selective ?1-adrenoceptor antagonists for concomitant cardiovascular and respiratory disease. FASEB J. 2017;31:3150-3166 pubmed publisher
    ..M., Woolard, J., Fromont, C., Jadhav, G. P., Mistry, S. N., Thompson, K. S. J., Kellam, B., Hill, S. J., Fischer, P. M. Novel selective ?1-adrenoceptor antagonists for concomitant cardiovascular and respiratory disease. ..
  2. Iqbal S, Lemmens Gruber R. Voltage gated ion channels blockade is the underlying mechanism of BIMU8 induced cardiotoxicity. Toxicol Lett. 2017;277:64-68 pubmed publisher
    ..87mV in fast inactivation of NaV1.5 channel. These experimental findings indicate that BIMU8 is a potent blocker of hERG, NaV1.5 and CaV1.2 cardiac ion channels thus revealing its proarrhythmic potential. ..
  3. Dong S, VanGelder K, Shi Z, Yu Y, Wu Z, Ferguson R, et al. Improvement of hERG-ROMK index of spirocyclic ROMK inhibitors through scaffold optimization and incorporation of novel pharmacophores. Bioorg Med Chem Lett. 2017;27:2559-2566 pubmed publisher
    ..In vivo evaluation of 32 demonstrated blood pressure lowering effects in the spontaneously hypertensive rat model. ..
  4. Bartolozzi A, Abeywardane A, Bosanac T, Broadwater J, Chen Z, Hutzler J, et al. Discovery and optimization of oxadiazole-based FLAP inhibitors. Bioorg Med Chem Lett. 2017;27:4652-4659 pubmed publisher
    ..Several compounds with favorable in vitro and in vivo properties were identified that were suitable for advanced profiling. ..
  5. Wang W, MacKinnon R. Cryo-EM Structure of the Open Human Ether-à-go-go-Related K+ Channel hERG. Cell. 2017;169:422-430.e10 pubmed publisher
    ..A subtle structural feature of the hERG selectivity filter might correlate with its fast inactivation rate, which is key to hERG's role in cardiac action potential repolarization. ..
  6. Salvino J, Srikanth Y, Lou R, Oyer H, Chen N, Kim F. Novel small molecule guanidine Sigma1 inhibitors for advanced prostate cancer. Bioorg Med Chem Lett. 2017;27:2216-2220 pubmed publisher
    ..Herein we report on a new series of Sigma1 compounds for lead optimization derived from a hybrid pharmacophore approach. ..
  7. Hyltén Cavallius L, Iepsen E, Wewer Albrechtsen N, Svendstrup M, Lubberding A, Hartmann B, et al. Patients With Long-QT Syndrome Caused by Impaired hERG-Encoded Kv11.1 Potassium Channel Have Exaggerated Endocrine Pancreatic and Incretin Function Associated With Reactive Hypoglycemia. Circulation. 2017;135:1705-1719 pubmed publisher
    ..Furthermore, glucose ingestion increased QT interval and aggravated the cardiac repolarization disturbances in LQT2 patients. URL: http://clinicaltrials.gov. Unique identifier: NCT02775513. ..
  8. Pillozzi S, Masselli M, Gasparoli L, D Amico M, Polletta L, Veltroni M, et al. Macrolide antibiotics exert antileukemic effects by modulating the autophagic flux through inhibition of hERG1 potassium channels. Blood Cancer J. 2016;6:e423 pubmed publisher
  9. Tester D, Ackerman M. Novel gene and mutation discovery in congenital long QT syndrome: let's keep looking where the street lamp standeth. Heart Rhythm. 2008;5:1282-4 pubmed publisher
  10. Kang J, Wang L, Chen X, Triggle D, Rampe D. Interactions of a series of fluoroquinolone antibacterial drugs with the human cardiac K+ channel HERG. Mol Pharmacol. 2001;59:122-6 pubmed
    ..HERG channel affinity should be an important criterion for the development of newer fluoroquinolones. ..
  11. Parent L. A helical segment makes potassium channels go-go. J Biol Chem. 2017;292:7706-7707 pubmed publisher
    ..Matthew D. Perry and colleagues now combine NMR spectroscopy and electrophysiological experiments to explore the functional properties of mutations within an overlooked hERG helix, finding important contributions to channel function. ..
  12. Radchenko E, Rulev Y, Safanyaev A, Palyulin V, Zefirov N. Computer-aided estimation of the hERG-mediated cardiotoxicity risk of potential drug components. Dokl Biochem Biophys. 2017;473:128-131 pubmed publisher
    ..45 for affinity and N = 2886, Q 2 = 0.60, RMSE cv = 0.55 for channel inhibition) are superior to the previously published models and can be used to minimize the risk of cardiotoxicity during drug development. ..
  13. Liu Q, Shi Q, Marcoux D, Batt D, Cornelius L, Qin L, et al. Identification of a Potent, Selective, and Efficacious Phosphatidylinositol 3-Kinase ? (PI3K?) Inhibitor for the Treatment of Immunological Disorders. J Med Chem. 2017;60:5193-5208 pubmed publisher
    ..Our lead molecule is very potent in PK/PD assays and highly efficacious in a mouse collagen-induced arthritis model. ..
  14. Issa N, Fisher W, Narayanan J. QT interval prolongation in a patient with LQT2 on levetiracetam. Seizure. 2015;29:134-6 pubmed publisher
  15. Teschemacher A, Seward E, Hancox J, Witchel H. Inhibition of the current of heterologously expressed HERG potassium channels by imipramine and amitriptyline. Br J Pharmacol. 1999;128:479-85 pubmed
    ..Inhibition of IHERG by the prototype TCAs imipramine and amitriptyline may suggest a mechanism for QT prolongation associated with risks of arrhythmia and sudden death that accompany high concentrations of TCAs following overdose. ..