Deconstruction of an African folk medicine uncovers a novel molecular strategy for therapeutic potassium channel activation

Angele De Silva, Rian Manville, Geoffrey Abbott

Research output: Contribution to journalArticle

Abstract

A third of the global population relies heavily upon traditional or folk medicines, such as the African shrub Mallotus oppositifolius. Here, we used pharmacological screening and electrophysiological analysis in combination with in silico docking and site-directed mutagenesis to elucidate the effects of M. oppositifolius constituents on KCNQ1, a ubiquitous and influential cardiac and epithelial voltage-gated potassium (Kv) channel. Two components of the M. oppositifolius leaf extract, mallotoxin (MTX) and 3-ethyl-2-hydroxy-2-cyclopenten-1-one (CPT1), augmented KCNQ1 current by negative shifting its voltage dependence of activation. MTX was also highly effective at augmenting currents generated by KCNQ1 in complexes with native partners KCNE1 or SMIT1; conversely, MTX inhibited KCNQ1-KCNE3 channels. MTX and CPT1 activated KCNQ1 by hydrogen bonding to the foot of the voltage sensor, a previously unidentified drug site which we also find to be essential for MTX activation of the related KCNQ2/3 channel. The findings elucidate the molecular mechanistic basis for modulation by a widely used folk medicine of an important human Kv channel and uncover novel molecular approaches for therapeutic modulation of potassium channel activity.
Original languageEnglish
Article numbereaav0824
JournalScience Advances Today
Volume4
Issue number11
DOIs
Publication statusPublished - 14 Nov 2018

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African Traditional Medicine
Potassium Channels
Traditional Medicine
Voltage-Gated Potassium Channels
Myeloma Proteins
Hydrogen Bonding
Site-Directed Mutagenesis
Computer Simulation
Foot
Therapeutics
Pharmacology
Pharmaceutical Preparations
Population

Bibliographical note

Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).
This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.

Cite this

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abstract = "A third of the global population relies heavily upon traditional or folk medicines, such as the African shrub Mallotus oppositifolius. Here, we used pharmacological screening and electrophysiological analysis in combination with in silico docking and site-directed mutagenesis to elucidate the effects of M. oppositifolius constituents on KCNQ1, a ubiquitous and influential cardiac and epithelial voltage-gated potassium (Kv) channel. Two components of the M. oppositifolius leaf extract, mallotoxin (MTX) and 3-ethyl-2-hydroxy-2-cyclopenten-1-one (CPT1), augmented KCNQ1 current by negative shifting its voltage dependence of activation. MTX was also highly effective at augmenting currents generated by KCNQ1 in complexes with native partners KCNE1 or SMIT1; conversely, MTX inhibited KCNQ1-KCNE3 channels. MTX and CPT1 activated KCNQ1 by hydrogen bonding to the foot of the voltage sensor, a previously unidentified drug site which we also find to be essential for MTX activation of the related KCNQ2/3 channel. The findings elucidate the molecular mechanistic basis for modulation by a widely used folk medicine of an important human Kv channel and uncover novel molecular approaches for therapeutic modulation of potassium channel activity.",
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Deconstruction of an African folk medicine uncovers a novel molecular strategy for therapeutic potassium channel activation. / De Silva, Angele; Manville, Rian; Abbott, Geoffrey.

In: Science Advances Today, Vol. 4, No. 11, eaav0824, 14.11.2018.

Research output: Contribution to journalArticle

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