Inhibitory effect of atomoxetine on Nav1.2 voltage-gated sodium channel currents

BackgroundAtomoxetine (ATX), a norepinephrine reuptake inhibitor (NRI), is used to attenuate the symptoms of Attention Deficit/Hyperactivity Disorder (AD/HD) by increasing neurotransmitter concentrations at the synaptic cleft. Although Nav1.2 voltage-gated sodium channels (VGSCs) are thought to play a role in monoamine transmitter release in the synaptic junction, it is unclear how atomoxetine affects Nav1.2 VGSCs.MethodsIn this study, we investigated the effect of ATX on Nav1.2 VGSC-transfected HEK293 cells with the whole-patch clamp technique.ResultsNav1.2 VGSC current decreased by 51.15 +/- 12.75% under treatment with 50 mu M ATX in the resting state (holding membrane potential at - 80 mV). The IC50 of ATX against Nav1.2 VGSC current was 45.57 mu M. The activation/inactivation curve of Nav1.2 VGSC currents was shifted toward hyperpolarization by 50 mu M ATX. In addition, the inhibitory effect of ATX increased with membrane depolarization (holding membrane potential at - 50 mV) and its IC50 was 10.16 mu M. Moreover, ATX showed the time-dependent interaction in the inactivation state.ConclusionThese findings suggest that ATX interacts with Nav1.2 VGSCs producing the inhibition of current and the modification of kinetic properties in the state-dependent manner.