The ubiquitous flavonoid quercetin is an atypical KCNQ potassium channel activator

Abstract

Many commonly consumed plants are used as folk medicines, often with unclear molecular mechanisms. Recent studies uncovered the ubiquitous and influential KCNQ family of voltage-gated potassium (Kv) channels as a therapeutic target for several medicinal plant compounds. Capers - immature flower buds of Capparis spinosa - have been consumed for food and medicinal purposes for millennia. Here, we show that caper extract hyperpolarizes cells expressing KCNQ1 or KCNQ2/3 Kv channels. Capers are the richest known natural source of quercetin, the most consumed dietary flavonoid. Quercetin potentiated KCNQ1/KCNE1, KCNQ2/3 and KCNQ4 currents but, unusually, not KCNQ5. Strikingly, quercetin augmented both activation and inactivation of KCNQ1, via a unique KCNQ activation mechanism involving sites atop the voltage sensor and in the pore. The findings uncover a novel potential molecular basis for therapeutic effects of quercetin-rich foods and a new chemical space for atypical modes of KCNQ channel modulation.

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

“…We previously found that quercetin enhances both activation and inactivation of homomeric KCNQ1 channels, inducing visible voltage-dependent decay at depolarized potentials (Redford and Abbott, 2020), recapitulated here (Figure 9F). We applied a combination of tannic acid and quercetin to KCNQ1 and found that the combination was not as effective as tannic acid alone in inducing constitutive current, but the current at less hyperpolarized potentials was inhibited more effectively than for either compound alone.…”

“…The five plants most effective at negative-shifting KCNQ2/3 activation V 0.5 were A. menziesii , A. glandulosa , U. dioica, P. munitum , and H. maximum ( Figure 3D ). Prior analyses of A. menziesii and other Arbutus species leaf extracts ( Kabadi and Hammarlund, 1963 ; Kouki and Manetas, 2002 ; Zitouni et al, 2020a , b ) revealed tannic acid as a principal component, together with compounds related to quercetin, which we previously found to activate KCNQ2/3 ( Redford and Abbott, 2020 ) (quercetrin, quercetin 3-β- D -glucoside and quercetin 3-O-α- L -arabinopyranoside), gallic acid, and avicularin. In addition, the glycosylated hydroquinone arbutin has been identified as the major abundant bioactive component in leaves of closely related Arbutus unedo ( Kabadi and Hammarlund, 1963 ; Tenuta et al, 2019 ).…”

“…Gallic acid had much weaker effects than tannic acid at 100 μM ( Figure 5 ) but we studied it further, as in previous studies of plants we discovered summative or synergistic effects of their constitutive compounds on specific channels ( Manville and Abbott, 2018 ; Redford and Abbott, 2020 ). In silico docking predicted that in contrast to tannic acid, the much smaller gallic acid (170 Da, versus 1700 Da for tannic acid) is capable of adopting different binding positions, one close to KCNQ2/3-R213/R242 and one close to KCNQ2/3 S5 tryptophan W236/W265 (with which gallic acid is predicted to hydrogen bond) ( Figures 8F–H ).…”

“…We previously found that quercetin negative-shifts the midpoint voltage-dependence of KCNQ1 and KCNQ2/3 activation ( Redford and Abbott, 2020 ). Prior KCNQ1 docking and KCNQ1 and KCNQ2/3 mutagenesis data were consistent with quercetin binding sites on the VSD and F340 on S6, rather than in the retigabine/GABA binding pocket ( Redford and Abbott, 2020 ).…”

KCNQ5 Potassium Channel Activation Underlies Vasodilation by Tea

“…Because it seemed unlikely that GTE was inducing inactivation in a non-inactivating channel [ 30 ], we next investigated the impact GTE had on endogenous oocyte currents ( Fig. 1J ).…”