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

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 α-hSlo. Results: NGEN increased M-type K⁺ current (I_K(M)) in a concentration-dependent manner with an EC₅₀ value of 9.8 μM 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 μM) 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 α-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⁺ (BK_Ca) 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 BK_Ca 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 K_M and BK_Ca channels caused by NGEN might combine to influence neuronal activity if similar channels were functionally co-expressed in central neurons in vivo.