Modulation of the transient outward current (I_to) in rat cardiac myocytes and human K_v4.3 channels by mefloquine

The antimalarial drug mefloquine, is known to be a potassium channel blocker, although its mechanism of action has not being elucidated and its effects on the transient outward current (I_to) and the molecular correlate, the K_v4.3 channel has not being studied. Here, we describe the mefloquine-induced inhibition of the rat ventricular I_to and of CHO cells co-transfected with human K_v4.3 and its accessory subunit hKChIP2C by whole-cell voltage-clamp. Mefloquine inhibited rat I_to and hK_v4.3 + KChIP2C currents in a concentration-dependent manner with a limited voltage dependence and similar potencies (IC₅₀ = 8.9 μM and 10.5 μM for cardiac myocytes and K_v4.3 channels, respectively). In addition, mefloquine did not affect the activation of either current but significantly modified the hK_v4.3 steady-state inactivation and recovery from inactivation. The effects of this drug was compared with that of 4-aminopyridine (4-AP), a well-known potassium channel blocker and its binding site does not seem to overlap with that of 4-AP. - Highlights: • Mefloquine inhibited ventricular I_to and hK_v4.3 channels. IC₅₀ = 8.9 and 10.5 μM. • Inactivation and recovery from inactivation in the hK_v4.3 channels were modified by mefloquine. • Mefloquine displayed a higher affinity for the inactivated state. • The binding site for mefloquine may be located in the extracellular side of the channel.