Ancient and modern anticonvulsants act synergistically in a KCNQ potassium channel binding pocket

Manville, Rían W.; Abbott, Geoffrey W.

doi:10.1038/s41467-018-06339-2

Cited by 39 publications

(54 citation statements)

References 47 publications

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“…As for (E)-2-dodecenal ( Fig. 5), the importance for mallotoxin binding of R213 outweighs that of W236, as determined using site-directed mutagenesis and TEVC of wild-type and mutant KCNQ2/3 channels (11,41). Interestingly, mutation of human KCNQ2-R213 is associated with benign familial neonatal convulsions (54), and the residue represents a hinge point between the pore module and the VSD.…”

Section: Discussionmentioning

confidence: 97%

“…Voltage-gated potassium (Kv) channels within the Kv channel subfamily Q (KCNQ), also termed the Kv7 subfamily, are sensitive to activation by a range of small molecules, including synthetic drugs, neurotransmitters, and metabolites (9)(10)(11)(12)(13). Kv channels, including the 5 isoforms within the KCNQ (Kv7) subfamily, are composed of tetramers of pore-forming (a) subunits, each consisting of 6 transmembrane segments (S): S1-4 comprise the voltage-sensing domain (VSD), and S5-6 comprise the pore module ( Fig.…”

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confidence: 99%

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Cilantro leaf harbors a potent potassium channel–activating anticonvulsant

Manville

Abbott

2019

FASEB j.

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Herbs have a long history of use as folk medicine anticonvulsants, yet the underlying mechanisms often remain unknown. Neuronal voltage‐gated potassium channel subfamily Q (KCNQ) dysfunction can cause severe epileptic encephalopathies that are resistant to modern anticonvulsants. Here we report that cilantro (Coriandrum sativum), a widely used culinary herb that also exhibits antiepileptic and other therapeutic activities, is a highly potent KCNQ channel activator. Screening of cilantro leaf metabolites revealed that one, the long‐chain fatty aldehyde (E)‐2‐dodecenal, activates multiple KCNQs, including the predominant neuronal isoform, KCNQ2/ KCNQ3 [half maximal effective concentration (EC50), 60 ± 20 nM], and the predominant cardiac isoform, KCNQ1 in complexes with the type I transmembrane ancillary subunit (KCNE1) (EC50, 260 ± 100 nM). (E)‐2‐dodecenal also recapitulated the anticonvulsant action of cilantro, delaying pentylene tetrazole‐induced seizures. In silico docking and mutagenesis studies identified the (E)‐2‐dodecenal binding site, juxtaposed between residues on the KCNQ S5 transmembrane segment and S4‐5 linker. The results provide a molecular basis for the therapeutic actions of cilantro and indicate that this ubiquitous culinary herb is surprisingly influential upon clinically important KCNQ channels.—Manville, R. W., Abbott, G. W. Cilantro leaf harbors a potent potassium channel‐activating anticonvulsant. FASEB J. 33, 11349–11363 (2019). http://www.fasebj.org

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Section: Discussionmentioning

confidence: 97%

mentioning

confidence: 99%

Cilantro leaf harbors a potent potassium channel–activating anticonvulsant

Manville

Abbott

2019

FASEB j.

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“…We also recently found that some plant metabolites can hyperpolarize KCNQ channel activation voltage dependence by binding to an arginine (e.g., R242 in KCNQ3) at the foot of S4, abutting the S4-5 linker (Fig. 5b) [20][21][22][23] . More recently, we found that this arginine also influences GABA binding 23 .…”

Section: Resultsmentioning

confidence: 92%

“…org/. Illustrations of KCNQ structure were based on the X. laevis KCNQ1 cryoEM structure 33 , which we altered to incorporate KCNQ3 residues known to be important for GABA and mallotoxin binding 8,20,21 , followed by energy minimization using the GROMOS 43B1 force field 34 , in DeepView 35 . Thus, X. laevis KCNQ1 amino acid sequence LITTLYIGF was converted to LITAWYIGF, the underlined W being W265 in human KCNQ3.…”

Section: Discussionmentioning

confidence: 99%

Potassium channels act as chemosensors for solute transporters

Manville

Abbott

2020

Commun Biol

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Potassium channels form physical complexes with solute transporters in vivo, yet little is known about their range of possible signaling modalities and the underlying mechanisms. The KCNQ2/3 potassium channel, which generates neuronal M-current, is voltage-gated and its activity is also stimulated by binding of various small molecules. KCNQ2/3 forms reciprocally regulating complexes with sodium-coupled myo-inositol transporters (SMITs) in mammalian neurons. Here, we report that the neurotransmitter γ-aminobutyric acid (GABA) and other small molecules directly regulate myo-inositol transport in rat dorsal root ganglia, and by human SMIT1-KCNQ2/3 complexes in vitro, by inducing a distinct KCNQ2/3 pore conformation. Reciprocally, SMIT1 tunes KCNQ2/3 sensing of GABA and related metabolites. Ion permeation and mutagenesis studies suggest that SMIT1 and GABA similarly alter KCNQ2/3 pore conformation but via different KCNQ subunits and molecular mechanisms. KCNQ channels therefore act as chemosensors to enable co-assembled myo-inositol transporters to respond to diverse stimuli including neurotransmitters, metabolites and drugs.

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“…However, little progress has been made in understanding the analgesic effects of Kv7/M channel openers in gout arthritis pain. Recently, numerous compounds have been reported to activate KCNQ/M channels [28][29][30][31][32]. In particular, retigabine and flupirtine are the best described neuronal M current activators.…”

Section: Discussionmentioning

confidence: 99%

Antinociceptive Efficacy of Retigabine and Flupirtine for Gout Arthritis Pain

et al. 2020

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Introduction: Gout arthritis is an inflammatory disease characterized by severe acute pain. The goal of pharmacological gout arthritis treatments is to reduce pain, and thereby increase the patient's quality of life. The Kv7/M channel activators retigabine and flupirtine show analgesic efficacy in animal models of osteoarthritic pain. We hypothesized that these drugs may also alleviate gout arthritis pain. Objective: To determine the effects of retigabine and flupirtine on pain behavior associated with monosodium urate (MSU)-induced gout arthritis. Methods: The gout arthritis model was established with an intra-articular injection of MSU into the right ankle joint, animals were treated with retigabine or flupirtine, and pain-related behaviors were assessed. Results: Retigabine and flupirtine significantly increased the mechanical threshold and prolonged the paw withdrawal latency in a rat model of gout arthritis pain in a dose-dependent manner. The antinociceptive effects of retigabine and flupirtine were fully antagonized by the Kv7/M channel blocker XE991. Conclusion: Retigabine and flupirtine showed antinociceptive effects for MSU-induced gout pain at different times during pain development.

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Ancient and modern anticonvulsants act synergistically in a KCNQ potassium channel binding pocket

Cited by 39 publications

References 47 publications

Cilantro leaf harbors a potent potassium channel–activating anticonvulsant

Cilantro leaf harbors a potent potassium channel–activating anticonvulsant

Potassium channels act as chemosensors for solute transporters

Antinociceptive Efficacy of Retigabine and Flupirtine for Gout Arthritis Pain

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