Evidence for Potentiation of M-Type Potassium Current by Flavonoid Corylin (3-(2,2-dimethylchromen-6-yl)-7-hydroxychromen-4-one)

Corylin (3-(2,2-dimethylchromen-6-yl)-7-hydroxychromen-4-one), a bioactive flavonoid, has been reported to exercise anti-inflammatory, anti-neoplastic, and antioxidant effects, and may also possess lifespan-extending properties. However, any modifications of transmembrane ionic currents produced by corylin remain largely unknown. In pituitary GH3 somatolactotrophs, we found that the presence of corylin concentration-dependently augmented the magnitude of M-type K+ current (IK(M)) with effective EC50 of 3.8 μM; concurrently, a shortening in activation time constant of the current was observed in its presence. Further addition of linopirdine (10 μM), an inhibitor of IK(M), but still in the presence of 10 μM corylin, almost fully suppressed IK(M) amplitude. Application of this compound induced a leftward shift in the steady-state activation curve of IK(M). The amplitude of IK(M) elicited during pulse train stimulation was enhanced in its presence. The exposure to corylin could augment hysteretic strength of IK(M) evoked by the long-lasting triangular ramp pulse; and corylin-enhanced strength was attenuated by further addition of linopirdine. Corylin-stimulated IK(M) failed to be altered by subsequent addition of either carvedilol or iberiotoxin, but it was attenuated by dapagliflozin. The depolarization-activated IK(M) was not affected by the presence of 17β-estradiol alone. Under cell-attached current recordings, the corylin application to bath increased the activity of M-type K+ (KM) channels with minimal change in single-channel amplitude; however, the mean open time of the channel became lengthened in its presence. Corylin-stimulated KM-channel activity was reversed by subsequent addition of either linopirdine or dapagliflozin. The erg-mediated current in GH3 cells was slightly inhibited by exposure to corylin. The docking analysis showed the ability of corylin to bind to certain residues in KCNQ2 or KCNH2 by using hydrogen bond and hydrophobic contact. Collectively, the present findings provide evidence that corylin modulates ionic currents, with KM (or KCNQ/KV7) channels serving as a key target underlying its in-vivo actions, as well as those of structurally related flavonoids. The ability of corylin or similar compounds to regulate ionic currents may contribute to their effects on the functional activities of neuronal, neuroendocrine or endocrine cells.