Ability of naringenin, a bioflavonoid, to activate M-type potassium current in motor neuron-like cells and to increase BKCa-channel activity in HEK293T cells transfected with α-hSlo subunit

Background: Naringenin (NGEN) is a citrus bioflavonoid known to have beneficial health properties; however, the ionic mechanism of its actions remains largely unclear. In this study, we attempted to evaluate the possible effects of NGEN on K+ currents in NSC-34 neuronal cells and in HEK293T cells expressing alpha-hSlo. Results: NGEN increased M-type K+ current (I-K(M)) in a concentration-dependent manner with an EC50 value of 9.8 mu M in NSC-34 cells. NGEN shifted the activation curve of I-K(M) conductance to the more negative potentials. In cell-attached recordings, NGEN or flupirtine enhanced the activity of M-type K+ (K-M) channels with no changes in single-channel amplitude. NGEN (10 mu M) had minimal effect on erg-mediated K+ currents. Under cell-attached voltage-clamp recordings, NGEN decreased the frequency of spontaneous action currents and further application of linopirdine can reverse NGEN-induced inhibition of firing. In HEK293T cells expressing alpha-hSlo, this compound increased the amplitude of Ca2+-activated K+ current (I-K(Ca)). Under inside-out recordings, NGEN applied to the intracellular side of the detached patch enhanced the activity of large-conductance Ca2+-activated K+ (BKCa) channels. Moreover, from the study of a modeled neuron, burst firing of simulated action potentials (APs) was reduced in the presence of the increased conductances of both K-M and K-Ca channels. Fast-slow analysis of AP bursting from this model also revealed that as the conductances of both K-M and BKCa channels were increased by two-fold, the voltage nullcline was shifted in an upward direction accompanied by the compression of burst trajectory. Conclusions: The present results demonstrate that activation of both KM and BKCa channels caused by NGEN might combine to influence neuronal activity if similar channels were functionally co-expressed in central neurons in vivo.