Deconstruction of an African folk medicine uncovers a novel molecular strategy for therapeutic potassium channel activation
| Autor: | Angele De Silva, Geoffrey W. Abbott, Rían W. Manville |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Physiology Mutagenesis (molecular biology technique) Cyclopentanes Pharmacology Mallotus oppositifolius Kv channel Xenopus laevis 03 medical and health sciences Global population 0302 clinical medicine Animals Humans Benzopyrans Protein Interaction Domains and Motifs Health and Medicine Research Articles Folk medicine Multidisciplinary biology Plant Extracts Chemistry fungi food and beverages Acetophenones SciAdv r-articles biology.organism_classification Potassium channel 3. Good health Potassium channel activity Electrophysiology 030104 developmental biology Potassium Channels Voltage-Gated KCNQ1 Potassium Channel Oocytes Potassium Medicine Traditional Ion Channel Gating 030217 neurology & neurosurgery Research Article |
| Zdroj: | De Silva, Angele M; Manville, Rian W; & Abbott, Geoffrey W. (2018). Deconstruction of an African folk medicine uncovers a novel molecular strategy for therapeutic potassium channel activation. SCIENCE ADVANCES, 4(11), eaav0824. doi: 10.1126/sciadv.aav0824. UC Irvine: Retrieved from: http://www.escholarship.org/uc/item/8zq9p91p Science Advances |
| ISSN: | 2375-2548 |
| DOI: | 10.1126/sciadv.aav0824 |
| Popis: | Analysis of a leaf extract used in African folk medicine reveals a high-affinity K+ channel agonist and its binding site. 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. |
| Databáze: | OpenAIRE |
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