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Biaryl sulfonamide ...
Biaryl sulfonamide motifs up- or down-regulate ion channel activity by activating voltage sensors
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- Liin, Sara (författare)
- Linköpings universitet,Avdelning för neurobiologi,Medicinska fakulteten
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- Lund, Per-Eric (författare)
- Linköpings universitet,Avdelningen för cellbiologi,Medicinska fakulteten
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- Larsson, Johan (författare)
- Linköpings universitet,Avdelning för neurobiologi,Medicinska fakulteten
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- Brask, Johan (författare)
- Linköpings universitet,Avdelning för neurobiologi,Medicinska fakulteten
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- Wallner, Björn (författare)
- Linköpings universitet,Bioinformatik,Tekniska fakulteten
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- Elinder, Fredrik (författare)
- Linköpings universitet,Avdelning för neurobiologi,Medicinska fakulteten
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(creator_code:org_t)
- 2018-07-12
- 2018
- Engelska.
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Ingår i: The Journal of General Physiology. - : ROCKEFELLER UNIV PRESS. - 0022-1295 .- 1540-7748. ; 150:8, s. 1215-1230
- Relaterad länk:
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https://doi.org/10.1...
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https://liu.diva-por... (primary) (Raw object)
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https://rupress.org/...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmakologi och toxikologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmacology and Toxicology (hsv//eng)
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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