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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,
Structural basis of action for a human ether-a-go-go-related gene 1 potassium channel activator.
2007,
Pubmed
,
Xenbase
Perry,
PD-118057 contacts the pore helix of hERG1 channels to attenuate inactivation and enhance K+ conductance.
2009,
Pubmed
,
Xenbase
Piper,
Gating currents associated with intramembrane charge displacement in HERG potassium channels.
2003,
Pubmed
,
Xenbase
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
Sanguinetti,
Predicting drug-hERG channel interactions that cause acquired long QT syndrome.
2005,
Pubmed
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
Schönherr,
Molecular determinants for activation and inactivation of HERG, a human inward rectifier potassium channel.
1996,
Pubmed
,
Xenbase
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
