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Molecular Pharmacology

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Research ArticleArticle

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)

Xulin Xu, Maurizio Recanatini, Marinella Roberti and Gea-Ny Tseng
Molecular Pharmacology June 2008, 73 (6) 1709-1721; DOI: https://doi.org/10.1124/mol.108.045591
Xulin Xu
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Maurizio Recanatini
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Marinella Roberti
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Gea-Ny Tseng
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Abstract

We studied the mechanisms and sites of activator actions of 2-[2-(3,4-dichloro-phenyl)-2,3-dihydro-1H-isoindol-5-ylamino]-nicotinic acid [PD307243 (PD)] and 1,3-bis-(2-hydroxy-5-trifluoromethyl-phenyl)-urea [NS1643 (NS)] on the human ether-a-go-go-related gene (hERG) channel expressed in oocytes and COS-7 cells. PD and NS affected hERG in a concentration-dependent manner, reaching a maximal increase in current amplitude by 100% and ≥300% (1-s test pulse to 0 mV), with apparent Kd values of 3 and 20 μM, respectively. Both drugs slowed hERG inactivation. NS additionally shifted the activation curve in the negative direction, accelerated activation, and slowed deactivation. Kinetic model simulations suggested that the activator effects of PD and NS could be largely accounted for by their effects on the hERG gating kinetics. Both drugs worked from outside the cell membrane but their binding sites seemed to be distinctly different. Perturbing the conformation of outer vestibule/external pore entrance (by cysteine substitution at high-impact positions or cysteine side chain modification at intermediate-impact positions) prevented the activator effect of NS but not that of PD. Furthermore, the peptide toxin BeKm-1, which bound to the outer mouth of the hERG channel, suppressed NS effect but potentiated PD effect. We propose that NS is a “gating-modifier”: it binds to the outer vestibule/pore entrance of hERG and increases current amplitudes by promoting channel activation while retarding inactivation. The activator effect of PD was prevented by external quaternary ammonium cations or dofetilide, which approached the hERG selectivity filter from opposite sides of the membrane and depleted K+ ions in the selectivity filter. We suggest that PD may work as a “pore-modifier” of the hERG channel.

Footnotes

  • This study was supported by R01-HL46451 and HL67840 (to G.N.T.) from the National Heart, Lung and Blood Institute of the National Institutes of Health.

  • ABBREVIATIONS: hERG, human ether-a-go-go-related gene; LQT2, long QT; aLQT, acquired LQT; RPR260243, (3R,4R)-4-(3-(6-methoxyquinolin-4-yl)-3-oxo-propyl)-1-(3-(2,3,5-trifluoro-phenyl)-prop-2-ynyl)-piperidine-3-carboxylic acid; NS, NS1643 (1,3-bis-(2-hydroxy-5-trifluoromethyl-phenyl)-urea); PD118057, 2-(4-(2-(3,4-dichlorophenyl)ethyl)phenylamino)benzoic acid; PD, PD307243 (2-[2-(3,4-dichloro-phenyl)-2,3-dihydro-1H-isoindol-5-ylamino]-nicotinic acid); TEA, tetraethylammonium; DTT, dithiothreitol; BeKm-1, toxin from Buthus eupeus venom; TPeA, tetrapentylammonium; TBA, tetrabutylammonium; QA, quaternary ammonium; WT, wild type; Vt, test pulse voltage; Vr, repolarization voltage.

    • Received January 22, 2008.
    • Accepted March 25, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 73 (6)
Molecular Pharmacology
Vol. 73, Issue 6
1 Jun 2008
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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 (PD…
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Research ArticleArticle

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)

Xulin Xu, Maurizio Recanatini, Marinella Roberti and Gea-Ny Tseng
Molecular Pharmacology June 1, 2008, 73 (6) 1709-1721; DOI: https://doi.org/10.1124/mol.108.045591

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Research ArticleArticle

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)

Xulin Xu, Maurizio Recanatini, Marinella Roberti and Gea-Ny Tseng
Molecular Pharmacology June 1, 2008, 73 (6) 1709-1721; DOI: https://doi.org/10.1124/mol.108.045591
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