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 enduring,
widespread medicinal use of witch hazel and fireweed and demonstrate a
screening strategy for discovering dual anti-inflammatory, analgesic small
molecules.