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Biosynthesis of a Flavonol from a Flavanone by Establishing a One-pot Bienzymatic Cascade
Published on: August 14, 2019
Flavonoid regulation of EAG1 channels
Anne E Carlson1, Tinatin I Brelidze, William N Zagotta
1Department of Physiology and Biophysics, University of Washington School of Medicine, Seattle, WA 98195, USA.
The Journal of General Physiology
|February 27, 2013
Summary
Four flavonoids, including fisetin and quercetin, were found to enhance the function of ether á go-go 1 (EAG1) channels. These compounds bind to the EAG1 channel
Area of Science:
- Ion channel physiology
- Molecular pharmacology
- Biochemistry
Background:
- The ether á go-go 1 (EAG1) channel, a voltage-gated potassium channel, regulates neuronal excitability and is implicated in cancer progression.
- EAG1 channels possess a cyclic nucleotide-binding homology domain (CNBHD) but lack known endogenous ligands or direct cyclic nucleotide regulation.
- Understanding EAG1 channel regulation is crucial for both neuroscience and oncology.
Purpose of the Study:
- To identify endogenous metabolites that modulate EAG1 channel activity.
- To elucidate the mechanism by which identified compounds regulate EAG1 channel gating.
- To explore the potential of EAG1 channels as a therapeutic target for flavonoid compounds.
Main Methods:
- Screening of biological metabolites for EAG1 channel modulators.
- Electrophysiological recordings to assess changes in channel gating.
- Fluorescence resonance energy transfer (FRET) and anisotropy-based binding assays to determine flavonoid-CNBHD interactions.
- Site-directed mutagenesis of the EAG1 CNBHD intrinsic ligand.
Main Results:
- Fisetin, quercetin, luteolin, and kaempferol were identified as EAG1 channel potentiators.
- These flavonoids shifted voltage dependence of activation to more hyperpolarizing potentials and slowed deactivation, with half-maximal concentrations of 2-8 µM.
- Flavonoids bound to the purified EAG1 CNBHD, and mutations mimicking intrinsic ligand displacement potentiated gating and enhanced flavonoid binding.
Conclusions:
- Flavonoids potentiate EAG1 channel activity by binding to the CNBHD, potentially by displacing its intrinsic ligand.
- The identified flavonoids represent a novel class of EAG1 channel regulators.
- EAG1 channels are a potential molecular target for the physiological effects of flavonoids, with implications for neurological and cancer therapies.
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