KCNQ and KCNE Isoform-Dependent Pharmacology Rationalizes Native American Dual Use of Specific Plants as Both Analgesics and Gastrointestinal Therapeutics.

Geoffrey W Abbott,Alexandra Kookootsedes,Rían W Manville,Kaitlyn E Redford,Grey Arena,Elliot Gunnison,Luiz Moreira,Emma Lasky,Kevin Tran,Ryan F Yoshimura

doi:10.3389/fphys.2021.777057

Geoffrey W Abbott, Alexandra Kookootsedes + Show 8 more

Open Access

https://doi.org/10.3389/fphys.2021.777057

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Abstract

Indigenous peoples of the Americas are proficient in botanical medicine. KCNQ family voltage-gated potassium (Kv) channels are sensitive to a variety of ligands, including plant metabolites. Here, we screened methanolic extracts prepared from 40 Californian coastal redwood forest plants for effects on Kv current and membrane potential in Xenopus oocytes heterologously expressing KCNQ2/3, which regulates excitability of neurons, including those that sense pain. Extracts from 9 of the 40 plant species increased KCNQ2/3 current at –60 mV by ≥threefold (maximally, 15-fold by Urtica dioica) and/or hyperpolarized membrane potential by ≥-3 mV (maximally, –11 mV by Arctostaphylos glandulosa). All nine plants have traditionally been used as both analgesics and gastrointestinal therapeutics. Of two extracts tested, both acted as KCNQ-dependent analgesics in mice. KCNQ2/3 activation at physiologically relevant, subthreshold membrane potentials by tannic acid, gallic acid and quercetin provided molecular correlates for analgesic action of several of the plants. While tannic acid also activated KCNQ1 and KCNQ1-KCNE1 at hyperpolarized, negative membrane potentials, it inhibited KCNQ1-KCNE3 at both negative and positive membrane potentials, mechanistically rationalizing historical use of tannic acid-containing plants as gastrointestinal therapeutics. KCNE dependence of KCNQ channel modulation by plant metabolites therefore provides a molecular mechanistic basis for Native American use of specific plants as both analgesics and gastrointestinal aids.

Highlights

The use of plants as medicines predates human history (Inskeep, 1969; Hardy et al, 2012; Weyrich et al, 2017)
In unclamped, KCNQ2/3-expressing oocytes (Figure 1C) and the fold-change induced by the extracts in tail currents at – 30 mV following a prepulse elicited by depolarization from –80 to –60 mV (Figure 1D)
As KCNQ2/3-dependent cell membrane hyperpolarization is expected to be the most important property for small molecules to KCNQ2/3-dependently reduce cellular excitability, we selected for further analysis the 9 plant extracts most effective at KCNQ2/3-dependent cellular hyperpolarization Urtica dioica (Common Nettle), Gaultheria shallon (Salal), Arctostaphylos glandulosa (Eastwood Manzanita), Polystichum munitum (Western Sword Fern), Sisyrinchium bellum (Western Blue-Eyed Grass), Rosa gymnocarpa (Dwarf Rose), Arbutus menziesii (Pacific Madrone), Heracleum maximum (Common Cow Parsnip), and Hedera canariensis (Algerian Ivy)

Summary

Introduction

The use of plants as medicines predates human history (Inskeep, 1969; Hardy et al, 2012; Weyrich et al, 2017). Indigenous peoples of North America have used thousands of plant species as medicines (Moerman, 2009). The Coast Miwok managed the various environments in this area, from beach to grassland to forest, and were adept at utilization of plants for a variety of purposes, including as food and medicine (Heizer and Whipple, 1971; Bean, 1994). Voltage-gated potassium (Kv) channels (Figure 1A) within the KCNQ (Kv7) subfamily were recently recognized as important targets for secondary metabolites found in medicinal plants used by indigenous peoples in areas including Africa, Asia, the Caribbean, and Latin America (Matschke et al, 2016; Manville and Abbott, 2018, 2019; Manville et al, 2019)

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