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

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...

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Autores principales:	Geoffrey W. Abbott, Kaitlyn E. Redford, Ryan F. Yoshimura, Rían W. Manville, Luiz Moreira, Kevin Tran, Grey Arena, Alexandra Kookootsedes, Emma Lasky, Elliot Gunnison
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	KCNQ channels KCNE subunits analgesia botanical medicines Native American Physiology QP1-981
Acceso en línea:	https://doaj.org/article/1d88ec059d934e06b7925c86bbc4cd3d
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spelling	oai:doaj.org-article:1d88ec059d934e06b7925c86bbc4cd3d2021-11-11T08:48:57ZKCNQ and KCNE Isoform-Dependent Pharmacology Rationalizes Native American Dual Use of Specific Plants as Both Analgesics and Gastrointestinal Therapeutics1664-042X10.3389/fphys.2021.777057https://doaj.org/article/1d88ec059d934e06b7925c86bbc4cd3d2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fphys.2021.777057/fullhttps://doaj.org/toc/1664-042XIndigenous 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.Geoffrey W. AbbottKaitlyn E. RedfordRyan F. YoshimuraRían W. ManvilleLuiz MoreiraKevin TranGrey ArenaAlexandra KookootsedesEmma LaskyElliot GunnisonFrontiers Media S.A.articleKCNQ channelsKCNE subunitsanalgesiabotanical medicinesNative AmericanPhysiologyQP1-981ENFrontiers in Physiology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	KCNQ channels KCNE subunits analgesia botanical medicines Native American Physiology QP1-981
spellingShingle	KCNQ channels KCNE subunits analgesia botanical medicines Native American Physiology QP1-981 Geoffrey W. Abbott Kaitlyn E. Redford Ryan F. Yoshimura Rían W. Manville Luiz Moreira Kevin Tran Grey Arena Alexandra Kookootsedes Emma Lasky Elliot Gunnison KCNQ and KCNE Isoform-Dependent Pharmacology Rationalizes Native American Dual Use of Specific Plants as Both Analgesics and Gastrointestinal Therapeutics
description	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.
format	article
author	Geoffrey W. Abbott Kaitlyn E. Redford Ryan F. Yoshimura Rían W. Manville Luiz Moreira Kevin Tran Grey Arena Alexandra Kookootsedes Emma Lasky Elliot Gunnison
author_facet	Geoffrey W. Abbott Kaitlyn E. Redford Ryan F. Yoshimura Rían W. Manville Luiz Moreira Kevin Tran Grey Arena Alexandra Kookootsedes Emma Lasky Elliot Gunnison
author_sort	Geoffrey W. Abbott
title	KCNQ and KCNE Isoform-Dependent Pharmacology Rationalizes Native American Dual Use of Specific Plants as Both Analgesics and Gastrointestinal Therapeutics
title_short	KCNQ and KCNE Isoform-Dependent Pharmacology Rationalizes Native American Dual Use of Specific Plants as Both Analgesics and Gastrointestinal Therapeutics
title_full	KCNQ and KCNE Isoform-Dependent Pharmacology Rationalizes Native American Dual Use of Specific Plants as Both Analgesics and Gastrointestinal Therapeutics
title_fullStr	KCNQ and KCNE Isoform-Dependent Pharmacology Rationalizes Native American Dual Use of Specific Plants as Both Analgesics and Gastrointestinal Therapeutics
title_full_unstemmed	KCNQ and KCNE Isoform-Dependent Pharmacology Rationalizes Native American Dual Use of Specific Plants as Both Analgesics and Gastrointestinal Therapeutics
title_sort	kcnq and kcne isoform-dependent pharmacology rationalizes native american dual use of specific plants as both analgesics and gastrointestinal therapeutics
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/1d88ec059d934e06b7925c86bbc4cd3d
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KCNQ and KCNE Isoform-Dependent Pharmacology Rationalizes Native American Dual Use of Specific Plants as Both Analgesics and Gastrointestinal Therapeutics

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