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Mol Pharmacol
2011 Oct 01;804:630-7. doi: 10.1124/mol.111.073809.
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Molecular determinants for activation of human ether-à-go-go-related gene 1 potassium channels by 3-nitro-n-(4-phenoxyphenyl) benzamide.
Garg V, Stary-Weinzinger A, Sachse F, Sanguinetti MC.
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Human ether-à-go-go-related gene 1 (hERG1) channels mediate repolarization of cardiac action potentials. Inherited long QT syndrome (LQTS) caused by loss-of-function mutations, or unintended blockade of hERG1 channels by many drugs, can lead to severe arrhythmia and sudden death. Drugs that activate hERG1 are a novel pharmacological approach to treat LQTS. 3-Nitro-n-(4-phenoxyphenyl) benzamide [ICA-105574 (ICA)] has been discovered to activate hERG1 by strong attenuation of pore-type inactivation. Here, we used scanning mutagenesis of hERG1 to identify the molecular determinants of ICA action. Three mutations abolished the activator effects of 30 μM ICA, including L622C in the pore helix, F557L in the S5 segment, and Y652A in the S6 segment. One mutation in S6 (A653M) switched the activity of ICA from an activator to an inhibitor, revealing its partial agonist activity. This was confirmed by showing that the noninactivating mutant hERG1 channel (G628C/S631C) was inhibited by ICA and that the addition of the F557L mutation rendered the channel drug-insensitive. Simulated molecular docking of ICA to homology models of hERG1 corroborated the scanning mutagenesis findings. Together, our findings indicate that ICA is a mixed agonist of hERG1 channels. Activation or inhibition of currents is mediated by the same or overlapping binding site located in the pore module between two adjacent subunits of the homotetrameric channel.
Berger,
Molecular dynamics simulations of a fluid bilayer of dipalmitoylphosphatidylcholine at full hydration, constant pressure, and constant temperature.
1997, Pubmed
Berger,
Molecular dynamics simulations of a fluid bilayer of dipalmitoylphosphatidylcholine at full hydration, constant pressure, and constant temperature.
1997,
Pubmed Bezanilla,
Gating currents.
1998,
Pubmed Brugada,
Sudden death associated with short-QT syndrome linked to mutations in HERG.
2004,
Pubmed Casis,
Mechanism of action of a novel human ether-a-go-go-related gene channel activator.
2006,
Pubmed
,
Xenbase Catterall,
Voltage-gated ion channels and gating modifier toxins.
2007,
Pubmed Cosconati,
Characterizing the 1,4-dihydropyridines binding interactions in the L-type Ca2+ channel: model construction and docking calculations.
2007,
Pubmed Cuello,
Structural mechanism of C-type inactivation in K(+) channels.
2010,
Pubmed Cuello,
Structural basis for the coupling between activation and inactivation gates in K(+) channels.
2010,
Pubmed Curran,
A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome.
1995,
Pubmed Fernandez,
Physicochemical features of the HERG channel drug binding site.
2004,
Pubmed
,
Xenbase Ficker,
Molecular determinants of dofetilide block of HERG K+ channels.
1998,
Pubmed
,
Xenbase Gerlach,
Pharmacological removal of human ether-à-go-go-related gene potassium channel inactivation by 3-nitro-N-(4-phenoxyphenyl) benzamide (ICA-105574).
2010,
Pubmed Goldenberg,
Long QT syndrome.
2008,
Pubmed Goldin,
Expression of ion channels by injection of mRNA into Xenopus oocytes.
1991,
Pubmed
,
Xenbase Hamill,
Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches.
1981,
Pubmed Hansen,
Activation of human ether-a-go-go-related gene potassium channels by the diphenylurea 1,3-bis-(2-hydroxy-5-trifluoromethyl-phenyl)-urea (NS1643).
2006,
Pubmed
,
Xenbase Hess,
GROMACS 4: Algorithms for Highly Efficient, Load-Balanced, and Scalable Molecular Simulation.
2008,
Pubmed Hockerman,
Molecular determinants of drug binding and action on L-type calcium channels.
1997,
Pubmed Jones,
Molecular recognition of receptor sites using a genetic algorithm with a description of desolvation.
1995,
Pubmed Kang,
Discovery of a small molecule activator of the human ether-a-go-go-related gene (HERG) cardiac K+ channel.
2005,
Pubmed Mitcheson,
A structural basis for drug-induced long QT syndrome.
2000,
Pubmed
,
Xenbase Perry,
PD-118057 contacts the pore helix of hERG1 channels to attenuate inactivation and enhance K+ conductance.
2009,
Pubmed
,
Xenbase Perry,
Structural basis of action for a human ether-a-go-go-related gene 1 potassium channel activator.
2007,
Pubmed
,
Xenbase Piper,
Gating currents associated with intramembrane charge displacement in HERG potassium channels.
2003,
Pubmed
,
Xenbase Sanguinetti,
Predicting drug-hERG channel interactions that cause acquired long QT syndrome.
2005,
Pubmed Sanguinetti,
hERG potassium channels and cardiac arrhythmia.
2006,
Pubmed Sanguinetti,
A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel.
1995,
Pubmed
,
Xenbase Schönherr,
Molecular determinants for activation and inactivation of HERG, a human inward rectifier potassium channel.
1996,
Pubmed
,
Xenbase Schreibmayer,
Voltage clamping of Xenopus laevis oocytes utilizing agarose-cushion electrodes.
1994,
Pubmed
,
Xenbase Schuster,
The IVS6 segment of the L-type calcium channel is critical for the action of dihydropyridines and phenylalkylamines.
1996,
Pubmed Smith,
The inward rectification mechanism of the HERG cardiac potassium channel.
1996,
Pubmed Stary,
Toward a consensus model of the HERG potassium channel.
2010,
Pubmed Stefani,
Cut-open oocyte voltage-clamp technique.
1998,
Pubmed
,
Xenbase Stühmer,
Electrophysiological recording from Xenopus oocytes.
1992,
Pubmed
,
Xenbase Tikhonov,
Structural model for dihydropyridine binding to L-type calcium channels.
2009,
Pubmed Trudeau,
HERG, a human inward rectifier in the voltage-gated potassium channel family.
1995,
Pubmed Witchel,
Troubleshooting problems with in vitro screening of drugs for QT interval prolongation using HERG K+ channels expressed in mammalian cell lines and Xenopus oocytes.
2002,
Pubmed
,
Xenbase Zachariae,
Side chain flexibilities in the human ether-a-go-go related gene potassium channel (hERG) together with matched-pair binding studies suggest a new binding mode for channel blockers.
2009,
Pubmed Zhou,
Novel potent human ether-a-go-go-related gene (hERG) potassium channel enhancers and their in vitro antiarrhythmic activity.
2005,
Pubmed Zou,
Single HERG delayed rectifier K+ channels expressed in Xenopus oocytes.
1997,
Pubmed
,
Xenbase
