Polymodal K+ channel modulation contributes to dual analgesic and anti-inflammatory actions of traditional botanical medicines

• Published in: Communications biology 2024-08, Vol.7 (1), p.1059-18, Article 1059
• Main Authors: Manville, Rían W., Yoshimura, Ryan F., Yeromin, Andriy V., Hogenkamp, Derk, van der Horst, Jennifer, Zavala, Angel, Chinedu, Sonia, Arena, Grey, Lasky, Emma, Fisher, Mark, Tracy, Christopher R., Othy, Shivashankar, Jepps, Thomas A., Cahalan, Michael D., Abbott, Geoffrey W.
• Format: Article
• Language: English
• Subjects: 631/443; 64; 64/60; 692/308; 9/74; 96; 96/31; Analgesics; Analgesics - chemistry; Analgesics - pharmacology; Animals; Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - pharmacology; Biomedical and Life Sciences; Channel gating; Coriandrum - chemistry; Hamamelidaceae; Humans; Indigenous species; Inflammation; Isoforms; Life Sciences; Lymphocytes T; Male; Medicinal plants; Mice; Molecular Docking Simulation; Molecular modelling; Mutagenesis; Pain perception; Plant extracts; Plant Extracts - chemistry; Plant Extracts - pharmacology; Plants, Medicinal - chemistry; Potassium Channel Blockers - chemistry; Potassium Channel Blockers - pharmacology; Potassium channels (voltage-gated); Quality of life; Tannins; Tannins - chemistry; Tannins - pharmacology
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-024-06752-y

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 - T-cell expressed Kv1.3 and nociceptive-neuron expressed Kv7.2/7.3. A subset of extracts both inhibits Kv1.3 and activates Kv7.2/7.3 at hyperpolarized potentials, effects predicted to be anti-inflammatory and analgesic, respectively. Among the top dual hits are witch hazel and fireweed; polymodal modulation of multiple K + channel types by hydrolysable tannins contributes to their dual anti-inflammatory, analgesic actions. In silico docking and mutagenesis data suggest 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. A dual potassium channel functional screen of 1444 plant extracts uncovers unexpected molecular mechanisms underlying the traditional use of witch hazel and fireweed as analgesic, anti-inflammatory medicines.