KCNQ5 activation is a unifying molecular mechanism shared by genetically and culturally diverse botanical hypotensive folk medicines

Rian Manville, Jennifer van der horst, Kaitlyn Redford, Benjamin Katz, Thomas Jepps, Geoffrey Abbott

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Botanical folk medicines have been used throughout human history to treat common disorders such as hypertension, often with unknown underlying mechanisms. Here, we discovered that hypotensive folk medicines from a genetically diverse range of plant species each selectively activated the vascular-expressed KCNQ5 potassium channel, a feature lacking in the modern synthetic pharmacopeia, whereas nonhypotensive plant extracts did not. Analyzing constituents of the hypotensive Sophora flavescens root, we found that the quinolizidine alkaloid aloperine is a KCNQ-dependent vasorelaxant that potently and isoform-selectively activates KCNQ5 by binding near the foot of the channel voltage sensor. Our findings reveal that KCNQ5-selective activation is a defining molecular mechanistic signature of genetically diverse traditional botanical hypotensives, transcending plant genus and human cultural boundaries. Discovery of botanical KCNQ5-selective potassium channel openers may enable future targeted therapies for diseases including hypertension and KCNQ5 loss-of-function encephalopathy.

Original languageEnglish
Pages (from-to)21236-21245
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number42
DOIs
Publication statusPublished - 30 Sep 2019

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Potassium Channels
Traditional Medicine
Quinolizidines
Sophora
Hypertension
Pharmacopoeias
Plant Extracts
Brain Diseases
Vasodilator Agents
Alkaloids
Blood Vessels
Foot
Protein Isoforms
History
Therapeutics
Transcend
aloperine

Keywords

  • herbal medicine
  • hypertension
  • potassium channel

Cite this

Manville, Rian ; van der horst, Jennifer ; Redford, Kaitlyn ; Katz, Benjamin ; Jepps, Thomas ; Abbott, Geoffrey. / KCNQ5 activation is a unifying molecular mechanism shared by genetically and culturally diverse botanical hypotensive folk medicines. In: Proceedings of the National Academy of Sciences of the United States of America. 2019 ; Vol. 116, No. 42. pp. 21236-21245.
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KCNQ5 activation is a unifying molecular mechanism shared by genetically and culturally diverse botanical hypotensive folk medicines. / Manville, Rian; van der horst, Jennifer; Redford, Kaitlyn; Katz, Benjamin; Jepps, Thomas; Abbott, Geoffrey.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 116, No. 42, 30.09.2019, p. 21236-21245.

Research output: Contribution to journalArticleResearchpeer-review

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