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Molecular Pharmacology

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Research ArticleArticle

ICA-105574 Interacts with a Common Binding Site to Elicit Opposite Effects on Inactivation Gating of EAG and ERG Potassium Channels

Vivek Garg, Anna Stary-Weinzinger and Michael C. Sanguinetti
Molecular Pharmacology April 2013, 83 (4) 805-813; DOI: https://doi.org/10.1124/mol.112.084384
Vivek Garg
Nora Eccles Harrison Cardiovascular Research & Training Institute, Department of Physiology, Department of Medicine, University of Utah, Salt Lake City, Utah (V.G., M.C.S.); and Department of Pharmacology and Toxicology, University of Vienna, Vienna, Austria (A.S.-W.)
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Anna Stary-Weinzinger
Nora Eccles Harrison Cardiovascular Research & Training Institute, Department of Physiology, Department of Medicine, University of Utah, Salt Lake City, Utah (V.G., M.C.S.); and Department of Pharmacology and Toxicology, University of Vienna, Vienna, Austria (A.S.-W.)
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Michael C. Sanguinetti
Nora Eccles Harrison Cardiovascular Research & Training Institute, Department of Physiology, Department of Medicine, University of Utah, Salt Lake City, Utah (V.G., M.C.S.); and Department of Pharmacology and Toxicology, University of Vienna, Vienna, Austria (A.S.-W.)
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Abstract

Rapid and voltage-dependent inactivation greatly attenuates outward currents in ether-a-go-go–related gene (ERG) K+ channels. In contrast, inactivation of related ether-a-go-go (EAG) K+ channels is very slow and minimally reduces outward currents. ICA-105574 (ICA, or 3-nitro-N-[4-phenoxyphenyl]-benzamide) has opposite effects on inactivation of these two channel types. Although ICA greatly attenuates ERG inactivation by shifting its voltage dependence to more positive potentials, it enhances the rate and extent of EAG inactivation without altering its voltage dependence. Here, we investigate whether the inverse functional response to ICA in EAG and ERG channels is related to differences in ICA binding site or to intrinsic mechanisms of inactivation. Molecular modeling coupled with site-directed mutagenesis suggests that ICA binds in a channel-specific orientation to a hydrophobic pocket bounded by the S5/pore helix/S6 of one subunit and S6 of an adjacent subunit. ICA is a mixed agonist of mutant EAG and EAG/ERG chimera channels that inactivate by a combination of slow and fast mechanisms. With the exception of three residues, the specific amino acids that form the putative binding pocket for ICA in ERG are conserved in EAG. Mutations introduced into EAG to replicate the ICA binding site in ERG did not alter the functional response to ICA. Together these findings suggest that ICA binds to the same site in EAG and ERG channels to elicit opposite functional effects. The resultant agonist or antagonist activity is determined solely by channel-specific differences in the mechanisms of inactivation gating.

Footnotes

  • This work was supported by the National Institutes of Health National Heart, Lung, and Blood Institute [Grant HL055236] (to M.S.); the American Heart Association (Western States Affiliate; postdoctoral fellowship to V.G.); and The Austrian Science Fund [Grant P22395] (to A.S.-W.).

  • dx.doi.org/10.1124/mol.112.084384.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Received December 11, 2012.
  • Accepted January 14, 2013.
  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 83 (4)
Molecular Pharmacology
Vol. 83, Issue 4
1 Apr 2013
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Research ArticleArticle

Activator Binding Site on Ether-A-Go-Go K+ Channels

Vivek Garg, Anna Stary-Weinzinger and Michael C. Sanguinetti
Molecular Pharmacology April 1, 2013, 83 (4) 805-813; DOI: https://doi.org/10.1124/mol.112.084384

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Research ArticleArticle

Activator Binding Site on Ether-A-Go-Go K+ Channels

Vivek Garg, Anna Stary-Weinzinger and Michael C. Sanguinetti
Molecular Pharmacology April 1, 2013, 83 (4) 805-813; DOI: https://doi.org/10.1124/mol.112.084384
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