Abstract
Most small-molecule inhibitors of voltage-gated ion channels display poor subtype specificity because they bind to highly conserved residues located in the channel's central cavity. Using a combined approach of scanning mutagenesis, electrophysiology, chemical ligand modification, chemical cross-linking, MS/MS-analyses and molecular modelling, we provide evidence for the binding site for adamantane derivatives and their putative access pathway in Kv7.1/KCNE1 channels. The adamantane compounds, exemplified by JNJ303, are highly potent gating modifiers that bind to fenestrations that become available when KCNE1 accessory subunits are bound to Kv7.1 channels. This mode of regulation by auxiliary subunits may facilitate the future development of potent and highly subtype-specific Kv channel inhibitors.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adamantane / analogs & derivatives*
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Adamantane / chemistry
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Adamantane / pharmacology*
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Allosteric Regulation / drug effects
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Animals
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Binding Sites
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Cross-Linking Reagents / chemistry
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Humans
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Ion Channel Gating / drug effects*
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KCNQ1 Potassium Channel / antagonists & inhibitors*
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KCNQ1 Potassium Channel / genetics
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KCNQ1 Potassium Channel / metabolism
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Models, Molecular
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Mutagenesis
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Mutation
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Oocytes
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Potassium Channel Blockers / chemistry
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Potassium Channel Blockers / pharmacology*
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Potassium Channels, Voltage-Gated / antagonists & inhibitors*
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Potassium Channels, Voltage-Gated / genetics
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Potassium Channels, Voltage-Gated / metabolism
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Tandem Mass Spectrometry
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Xenopus laevis
Substances
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Cross-Linking Reagents
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KCNE1 protein, human
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KCNQ1 Potassium Channel
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Potassium Channel Blockers
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Potassium Channels, Voltage-Gated
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Adamantane