Flavonoid Regulation of HCN2 Channels

Abstract

Background: HCN2 channels are regulated by membrane potential and by the direct binding of cyclic nucleotides to their carboxyl-terminal region. Results: The flavonoid fisetin potentiates HCN2 channel activation. Conclusion: Fisetin acts as a partial agonist for HCN2 channels by binding to the channel's cyclic nucleotide-binding site. Significance: HCN2 may be a target for the physiologic action of flavonoids such as fisetin.

Inhibition of transmembrane member 16A calcium‐activated chloride channels by natural flavonoids contributes to flavonoid anticancer effects

“…TMEM16A channels are not likely to be the sole mechanism responsible for flavonoid‐associated anticancer effects, as flavonoids are reported to modulate many different ion channels (e.g. hERG K + channels [Zitron et al, ] and ether á go‐go 1 channels [Carlson et al, ,b]), which may be involved in progression of cancer. In addition, Ca v 1.2 channels (Saponara et al, ), TRPC5 channels (Naylor et al, ) and HCN2 channels (Carlson et al, ,b) are also modulated by flavonoids.…”

“…hERG K + channels [Zitron et al, ] and ether á go‐go 1 channels [Carlson et al, ,b]), which may be involved in progression of cancer. In addition, Ca v 1.2 channels (Saponara et al, ), TRPC5 channels (Naylor et al, ) and HCN2 channels (Carlson et al, ,b) are also modulated by flavonoids. Therefore, based on the results from this study, we consider that TMEM16A channels may play an important role in the anticancer effects associated with flavonoids.…”

Evolution and Structural Characteristics of Plant Voltage-Gated K+ Channels

“…It is quite interesting that structure/function studies of EAG family K + channels reveal that the C-linker/CNBD complex retains a central role in regulating voltage gating even in channels that do not bind cyclic nucleotides. EAG family channel gating can be regulated by competition for the CNBD pocket between flavonoids and an intrinsic protein loop (Brelidze et al, 2012(Brelidze et al, , 2013Carlson et al, 2013a;Dai et al, 2018), and flavonoids also regulate the gating of HCN family channels (Carlson et al, 2013b). The abundance of flavonoids in plants (Winkel-Shirley, 2001;Mouradov and Spangenberg, 2014) raises the interesting possibility that flavonoids could be native ligands other than cyclic nucleotides for the CNBD pocket of plant VG K + channels or plant CNGCs.…”

A pharmacological basis of herbal medicines for epilepsy

“…Molecular effects of baicalin and wogonin include activation of TREK-2 two-pore domain [128] and large-conductance Ca 2+ -activated potassium channels (BK Ca ) [129], as well as inhibition of expression of TRPC1 channels [130]. Fisetin (2-(3,4-dihydroxyphenyl)-3,7-dihydroxychromen-4-one), which has been reported to exhibit anticonvulsant effects [131], was also found to potentiate the HCN2 channel [132]. Naringenin (5,7-dihydroxy-2-(4-hydroxyphenyl)chromen-4-one) has been reported to be a BK Ca channel opener [133].…”