Ancient and Modern Anticonvulsants Act Synergistically at the Same Potassium Channel Binding Pocket
Abstract number :
1.047
Submission category :
1. Basic Mechanisms / 1D. Mechanisms of Therapeutic Interventions
Year :
2018
Submission ID :
498433
Source :
www.aesnet.org
Presentation date :
12/1/2018 6:00:00 PM
Published date :
Nov 5, 2018, 18:00 PM
Authors :
Rian Manville, University of California - Irvine and Geoffrey W. Abbott, University of California - Irvine
Rationale: To uncover the molecular basis of centuries old herbal and traditional anticonvulsant remedies, including the African shrub Mallotus oppositifolius. Methods: In silico docking, mutagenesis, cellular electrophysiology and pentylenetetrazole-induced tonic seizure models. Results: Two components of M. oppositifolius leaf extract, mallotoxin (MTX) and isovaleric acid (IVA), act synergistically to open neuronal KCNQs, including KCNQ2/3 channels. Furthermore, MTX/IVA binding induces a stable KCNQ2/3 open state that increases the potency and efficacy of the anticonvulsant retigabine. Conclusions: Leveraging the synergy between ancient and modern anticonvulsants to exploit differential KCNQ isoform and open-state preferences, presents a novel approach to developing safe yet effective anticonvulsants. Funding: US National Institutes of Health (GM115189 to GWA)