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The amiodarone derivative KB130015 activates hERG1 potassium channels via a novel mechanism.
Gessner G
,
Macianskiene R
,
Starkus JG
,
Schönherr R
,
Heinemann SH
.
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Human ether à go-go related gene (hERG1) potassium channels underlie the repolarizing I(Kr) current in the heart. Since they are targets of various drugs with cardiac side effects we tested whether the amiodarone derivative 2-methyl-3-(3,5-diiodo-4-carboxymethoxybenzyl)benzofuran (KB130015) blocks hERG1 channels like its parent compound. Using patch-clamp and two-electrode voltage-clamp techniques we found that KB130015 blocks native and recombinant hERG1 channels at high voltages, but it activates them at low voltages. The activating effect has an apparent EC(50) value of 12microM and is brought about by an about 4-fold acceleration of activation kinetics and a shift in voltage-dependent activation by -16mV. Channel activation was not use-dependent and was independent of inactivation gating. KB130015 presumably binds to the hERG1 pore from the cytosolic side and functionally competes with hERG1 block by amiodarone, E4031 (N-[4-[[1-[2-(6-methyl-2-pyridinyl)ethyl]-4-piperidinyl] carbonyl] phenyl] methanesulfonamide dihydrochloride), and sertindole. Vice versa, amiodarone attenuates hERG1 activation by KB130015. Based on synergic channel activation by mallotoxin and KB130015 we conclude that the hERG1 pore contains at least two sites for activators that are functionally coupled among each other and to the cavity-blocker site. KB130015 and amiodarone may serve as lead structures for the identification of hERG1 pore-interacting drugs favoring channel activation vs. block.
Abitbol,
Stilbenes and fenamates rescue the loss of I(KS) channel function induced by an LQT5 mutation and other IsK mutants.
1999, Pubmed,
Xenbase
Abitbol,
Stilbenes and fenamates rescue the loss of I(KS) channel function induced by an LQT5 mutation and other IsK mutants.
1999,
Pubmed
,
Xenbase
Carlsson,
Synthesis and preliminary characterization of a novel antiarrhythmic compound (KB130015) with an improved toxicity profile compared with amiodarone.
2002,
Pubmed
Casis,
Mechanism of action of a novel human ether-a-go-go-related gene channel activator.
2006,
Pubmed
,
Xenbase
Chen,
Position of aromatic residues in the S6 domain, not inactivation, dictates cisapride sensitivity of HERG and eag potassium channels.
2002,
Pubmed
,
Xenbase
Doyle,
The structure of the potassium channel: molecular basis of K+ conduction and selectivity.
1998,
Pubmed
Fermini,
The impact of drug-induced QT interval prolongation on drug discovery and development.
2003,
Pubmed
Ficker,
Molecular determinants of dofetilide block of HERG K+ channels.
1998,
Pubmed
,
Xenbase
Gessner,
The amiodarone derivative 2-methyl-3-(3,5-diiodo-4-carboxymethoxybenzyl)benzofuran (KB130015) opens large-conductance Ca2+-activated K+ channels and relaxes vascular smooth muscle.
2007,
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
Hosaka,
Mutational analysis of block and facilitation of HERG current by a class III anti-arrhythmic agent, nifekalant.
2007,
Pubmed
,
Xenbase
Jiang,
Use-dependent 'agonist' effect of azimilide on the HERG channel.
1999,
Pubmed
,
Xenbase
Kamiya,
Short- and long-term effects of amiodarone on the two components of cardiac delayed rectifier K(+) current.
2001,
Pubmed
,
Xenbase
Kang,
Discovery of a small molecule activator of the human ether-a-go-go-related gene (HERG) cardiac K+ channel.
2005,
Pubmed
Kiehn,
Inhibitory effects of the class III antiarrhythmic drug amiodarone on cloned HERG potassium channels.
1999,
Pubmed
,
Xenbase
Kodama,
Amiodarone: ionic and cellular mechanisms of action of the most promising class III agent.
1999,
Pubmed
Long,
Crystal structure of a mammalian voltage-dependent Shaker family K+ channel.
2005,
Pubmed
Malykhina,
Fenamate-induced enhancement of heterologously expressed HERG currents in Xenopus oocytes.
2002,
Pubmed
,
Xenbase
McManus,
An activator of calcium-dependent potassium channels isolated from a medicinal herb.
1993,
Pubmed
Mitcheson,
A structural basis for drug-induced long QT syndrome.
2000,
Pubmed
,
Xenbase
Mubagwa,
KB130015, a new amiodarone derivative with multiple effects on cardiac ion channels.
2003,
Pubmed
Ottolia,
Potentiation of large conductance KCa channels by niflumic, flufenamic, and mefenamic acids.
1994,
Pubmed
Perry,
Structural basis of action for a human ether-a-go-go-related gene 1 potassium channel activator.
2007,
Pubmed
,
Xenbase
Ridley,
High affinity HERG K(+) channel blockade by the antiarrhythmic agent dronedarone: resistance to mutations of the S6 residues Y652 and F656.
2004,
Pubmed
Sanguinetti,
A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel.
1995,
Pubmed
,
Xenbase
Sanguinetti,
hERG potassium channels and cardiac arrhythmia.
2006,
Pubmed
Schönherr,
Inhibition of human ether à go-go potassium channels by Ca(2+)/calmodulin.
2000,
Pubmed
,
Xenbase
Schönherr,
Molecular determinants for activation and inactivation of HERG, a human inward rectifier potassium channel.
1996,
Pubmed
,
Xenbase
Seebohm,
Activators of cation channels: potential in treatment of channelopathies.
2005,
Pubmed
Thomas,
The cardiac hERG/IKr potassium channel as pharmacological target: structure, function, regulation, and clinical applications.
2006,
Pubmed
Trudeau,
HERG, a human inward rectifier in the voltage-gated potassium channel family.
1995,
Pubmed
Xu,
Probing the binding sites and mechanisms of action of two human ether-a-go-go-related gene channel activators, 1,3-bis-(2-hydroxy-5-trifluoromethyl-phenyl)-urea (NS1643) and 2-[2-(3,4-dichloro-phenyl)-2,3-dihydro-1H-isoindol-5-ylamino]-nicotinic acid (PD307243).
2008,
Pubmed
,
Xenbase
Zeng,
Mallotoxin is a novel human ether-a-go-go-related gene (hERG) potassium channel activator.
2006,
Pubmed
Zhou,
Potassium channel receptor site for the inactivation gate and quaternary amine inhibitors.
2001,
Pubmed
,
Xenbase
Zhou,
Novel potent human ether-a-go-go-related gene (hERG) potassium channel enhancers and their in vitro antiarrhythmic activity.
2005,
Pubmed