Polymodal potassium channel modulation contributes to dual analgesic and anti-inflammatory actions of ancient botanical medicines

Pain and inflammation contribute immeasurably to reduced quality of life, yet modern analgesic and anti-inflammatory therapeutics can cause dependence and side effects. Here, we screened 1444 plant extracts, prepared primarily from native species in California and the United States Virgin Islands, against two voltage-gated K+ channels - T38 cell expressed Kv1.3 and nociceptive-neuron expressed Kv7.2/7.3. A subset of extracts both inhibited Kv1.3, and activated Kv7.2/7.3 at hyperpolarized potentials, effects predicted to be anti-inflammatory and analgesic, respectively. Among the top dual hits were witch hazel and fireweed; polymodal modulation of multiple K+ channel types by hydrolysable tannins contributed to their dual anti-inflammatory, analgesic actions. In silico docking and mutagenesis data suggested pore-proximal extracellular linker sequence divergence underlies opposite effects of hydrolysable tannins on different Kv1 isoforms. The findings provide molecular insights into the e..., 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 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 extracts ..., , ## Source Data for manuscript: Polymodal potassium channel modulation contributes to dual analgesic and anti-inflammatory actions of ancient botanical medicines.

The datasets included are the original Excel files used to generate each panel for figures 1-7 & 9-10 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 samp...