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Biaryl sulfonamide motifs up- or down-regulate ion channel activity by activating voltage sensors.

ABSTRACT: Voltage-gated ion channels are key molecules for the generation of cellular electrical excitability. Many pharmaceutical drugs target these channels by blocking their ion-conducting pore, but in many cases, channel-opening compounds would be more beneficial. Here, to search for new channel-opening compounds, we screen 18,000 compounds with high-throughput patch-clamp technology and find several potassium-channel openers that share a distinct biaryl-sulfonamide motif. Our data suggest that the negatively charged variants of these compounds bind to the top of the voltage-sensor domain, between transmembrane segments 3 and 4, to open the channel. Although we show here that biaryl-sulfonamide compounds open a potassium channel, they have also been reported to block sodium and calcium channels. However, because they inactivate voltage-gated sodium channels by promoting activation of one voltage sensor, we suggest that, despite different effects on the channel gates, the biaryl-sulfonamide motif is a general ion-channel activator motif. Because these compounds block action potential-generating sodium and calcium channels and open an action potential-dampening potassium channel, they should have a high propensity to reduce excitability. This opens up the possibility to build new excitability-reducing pharmaceutical drugs from the biaryl-sulfonamide scaffold.

SUBMITTER: Liin SI

PROVIDER: S-EPMC6080886 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Biaryl sulfonamide motifs up- or down-regulate ion channel activity by activating voltage sensors.

Liin Sara I SI Lund Per-Eric PE Larsson Johan E JE Brask Johan J Wallner Björn B Elinder Fredrik F

The Journal of general physiology 20180712 8

Voltage-gated ion channels are key molecules for the generation of cellular electrical excitability. Many pharmaceutical drugs target these channels by blocking their ion-conducting pore, but in many cases, channel-opening compounds would be more beneficial. Here, to search for new channel-opening compounds, we screen 18,000 compounds with high-throughput patch-clamp technology and find several potassium-channel openers that share a distinct biaryl-sulfonamide motif. Our data suggest that the ne ...[more]

PMID: 30002162

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Dataset Information

Biaryl sulfonamide motifs up- or down-regulate ion channel activity by activating voltage sensors.

Publications

Biaryl sulfonamide motifs up- or down-regulate ion channel activity by activating voltage sensors.

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