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J Pharmacol Sci
2008 Nov 01;1083:301-7. doi: 10.1254/jphs.08102fp.
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Molecular determinants of hERG channel block by terfenadine and cisapride.
Kamiya K
,
Niwa R
,
Morishima M
,
Honjo H
,
Sanguinetti MC
.
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Block of cardiac hERG K+ channels by the antihistamine terfenadine and the prokinetic agent cisapride is associated with prolonged ventricular repolarization and an increased risk of ventricular arrhythmia. Here, we used a site-directed mutagenesis approach to determine the molecular determinants of hERG block by terfenadine and cisapride. Wild-type and mutant hERG channels were heterologously expressed in Xenopus laevis oocytes and characterized by measuring whole cell currents with two-microelectrode voltage clamp techniques. Mutation of T623, S624, Y652, or F656 to Ala reduced channel sensitivity to block by terfenadine. The same mutations reduced sensitivity to cisapride. These data confirm our previous findings that polar residues (T623, S624) located near the base of the pore helix and aromatic residues (Y652, F656) located in the S6 domain are key molecular determinants of the hERG drug binding site. Unlike methanesulfonanilides (dofetilide, MK-499, E-4031, ibutilide) or clofilium, mutation of V625, G648, or V659 did not alter the sensitivity of hERG channels to terfenadine or cisapride. As previously proposed by molecular modeling studies (Farid R, et al. Bioorg Med Chem. 2006;14:3160-3173), our findings suggest that different drugs can adopt distinct modes of binding to the central cavity of hERG.
Armstrong,
Interaction of tetraethylammonium ion derivatives with the potassium channels of giant axons.
1971, Pubmed
Armstrong,
Interaction of tetraethylammonium ion derivatives with the potassium channels of giant axons.
1971,
Pubmed
Chiu,
Validation of a [3H]astemizole binding assay in HEK293 cells expressing HERG K+ channels.
2004,
Pubmed
Curran,
A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome.
1995,
Pubmed
Diaz,
The [3H]dofetilide binding assay is a predictive screening tool for hERG blockade and proarrhythmia: Comparison of intact cell and membrane preparations and effects of altering [K+]o.
2004,
Pubmed
Farid,
New insights about HERG blockade obtained from protein modeling, potential energy mapping, and docking studies.
2006,
Pubmed
Fernandez,
Physicochemical features of the HERG channel drug binding site.
2004,
Pubmed
,
Xenbase
Ficker,
Molecular determinants of inactivation and dofetilide block in ether a-go-go (EAG) channels and EAG-related K(+) channels.
2001,
Pubmed
,
Xenbase
Finlayson,
[3H]dofetilide binding to HERG transfected membranes: a potential high throughput preclinical screen.
2001,
Pubmed
Guo,
Molecular determinants of cocaine block of human ether-á-go-go-related gene potassium channels.
2006,
Pubmed
Heginbotham,
Mutations in the K+ channel signature sequence.
1994,
Pubmed
,
Xenbase
Kamiya,
Molecular determinants of HERG channel block.
2006,
Pubmed
,
Xenbase
Kemp,
Antihistamines--is there anything safe to prescribe?
1992,
Pubmed
Lees-Miller,
Molecular determinant of high-affinity dofetilide binding to HERG1 expressed in Xenopus oocytes: involvement of S6 sites.
2000,
Pubmed
,
Xenbase
Milnes,
Blockade of HERG potassium currents by fluvoxamine: incomplete attenuation by S6 mutations at F656 or Y652.
2003,
Pubmed
Mitcheson,
A structural basis for drug-induced long QT syndrome.
2000,
Pubmed
,
Xenbase
Mitcheson,
Trapping of a methanesulfonanilide by closure of the HERG potassium channel activation gate.
2000,
Pubmed
,
Xenbase
Paul,
Inhibition of HERG potassium channel current by the class 1a antiarrhythmic agent disopyramide.
2001,
Pubmed
Perry,
Structural determinants of HERG channel block by clofilium and ibutilide.
2004,
Pubmed
,
Xenbase
Pratt,
Cardiovascular safety of fexofenadine HCl.
1999,
Pubmed
Pratt,
Cardiovascular safety of fexofenadine HCl.
1999,
Pubmed
Rajamani,
Pharmacological rescue of human K(+) channel long-QT2 mutations: human ether-a-go-go-related gene rescue without block.
2002,
Pubmed
Ridley,
Lidoflazine is a high affinity blocker of the HERG K(+)channel.
2004,
Pubmed
Ridley,
High affinity HERG K(+) channel blockade by the antiarrhythmic agent dronedarone: resistance to mutations of the S6 residues Y652 and F656.
2004,
Pubmed
Roy,
HERG, a primary human ventricular target of the nonsedating antihistamine terfenadine.
1996,
Pubmed
,
Xenbase
Sanguinetti,
Two components of cardiac delayed rectifier K+ current. Differential sensitivity to block by class III antiarrhythmic agents.
1990,
Pubmed
Sanguinetti,
A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel.
1995,
Pubmed
,
Xenbase
Sarkar,
The "megaprimer" method of site-directed mutagenesis.
1990,
Pubmed
Stork,
State dependent dissociation of HERG channel inhibitors.
2007,
Pubmed
,
Xenbase
Stühmer,
Electrophysiological recording from Xenopus oocytes.
1992,
Pubmed
,
Xenbase
Sánchez-Chapula,
Molecular determinants of voltage-dependent human ether-a-go-go related gene (HERG) K+ channel block.
2002,
Pubmed
,
Xenbase
Sánchez-Chapula,
Block of wild-type and inactivation-deficient human ether-a-go-go-related gene K+ channels by halofantrine.
2004,
Pubmed
,
Xenbase
Wang,
Modulation of HERG affinity for E-4031 by [K+]o and C-type inactivation.
1997,
Pubmed
,
Xenbase
Witchel,
The low-potency, voltage-dependent HERG blocker propafenone--molecular determinants and drug trapping.
2004,
Pubmed
,
Xenbase
