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Biaryl sulfonamide motifs up- or down-regulate ion channel activity by activating voltage sensors
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten.ORCID-id: 0000-0001-8493-0114
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten.ORCID-id: 0000-0003-3852-1015
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten.
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2018 (engelsk)Inngår i: The Journal of General Physiology, ISSN 0022-1295, E-ISSN 1540-7748, Vol. 150, nr 8, s. 1215-1230Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

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.

sted, utgiver, år, opplag, sider
ROCKEFELLER UNIV PRESS , 2018. Vol. 150, nr 8, s. 1215-1230
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URN: urn:nbn:se:liu:diva-150493DOI: 10.1085/jgp.201711942ISI: 000440815100015PubMedID: 30002162OAI: oai:DiVA.org:liu-150493DiVA, id: diva2:1241694
Merknad

Funding Agencies|Swedish Research Council [2016-02615]; Swedish Heart-Lung Foundation [20150672]; Swedish Brain Foundation [2016-0326]; Swedish Society for Medical Research

Tilgjengelig fra: 2018-08-24 Laget: 2018-08-24 Sist oppdatert: 2018-09-10

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