Discovery of a potent, Kv7.3-selective potassium channel opener from a Polynesian traditional botanical anticonvulsant

The voltage-gated potassium (Kv) channel formed by Kv7.2/3 (KCNQ2/3) heteromers is a major target for anticonvulsant drug development. Here, we screened 1,444 extracts primarily from plants collected in California and the US Virgin Islands, for their ability to activate Kv7.2/3 but not inhibit Kv1.3, to select against tannic acid being the active component. We validated the 7 strongest hits, identified Thespesia populnea (miro, milo, portia tree) as the most promising, then discovered its primary active metabolite to be gentisic acid (GA). GA highly potently activated Kv7.2/3 (EC50, 2.8 nM). GA is, uniquely, 100% selective for Kv7.3 versus other Kv7 homomers; it requires S5 residue Kv7.3-W265 for Kv7.2/3 activation, and it ameliorates pentylenetetrazole-induced seizures in mice. Also an active aspirin metabolite, GA provides a molecular rationale for the use of T. populnea as an anticonvulsant in Polynesian indigenous medicine and presents novel pharmacological prospects for potent, iso..., Collection of plant samplesWe collected, between 2019 and 2022, aerial parts of plants under permit from Mojave National Preserve (study # MOJA-00321), Yosemite National Park (study # YOSE-00839), Santa Monica Mountains National Recreation Area (study # SAMO-00192), Muir Woods National Monument (study # MUWO-00035), Santa Cruz Island and Santa Rosa Island (study # CHIS-0023), and Boyd Deep Canyon (Indian Wells, CA) (permit through Philip L. Boyd Deep Canyon. Desert Research 376 Center, University of California, Riverside, CA) in California, US. In USVI, we collected from Virgin Islands National Park, St. John (study # VIIS-20001), Salt River Bay National Historical Park and Ecological Preserve, St. Croix (study # SARI-00056) and Buck Island Reef National Monument, St. Croix (study # BUIS-00103). Plant samples were collected in a manner designed to not kill the remaining plant, sealed in Ziploc bags (SC Johnson, Racine, WI, US), kept cold, and frozen as soon as possible. Other plant extr..., , ## Source Data for manuscript: Discovery of a potent, Kv7.3-selective potassium channel opener from a Polynesian traditional botanical anticonvulsant.

The datasets included are the original Excel files used to generate each panel for figures 1-8 in this manuscript. The title of each Excel file is labeled to directly correspond to the figure in the manuscript:

Figure Number & panel > Channel Investigated > Condition > Parameter Measured

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The types of files included within this repository are as follows:

> Plant Screen
> This is a database providing the full details of all 1444 plant extracts screened for activity against Kv7.2/7.3 and Kv1.3 as summarized by the dot-plot in Figure 1A and Figure 1B. The database contains columns providing identifying information for each plant where appropriate. The information provided in each column is as follows:

Plant ID: Unique Identifier of the plant sample. The code corresponds to the region the sample was obtained and th...