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

Yoshihiko Nakatani, Kanami Ishikawa, Yuko Aoki, Takahiro Shimooki, Naoki Yamamoto, Taku Amano

Pharmacological reports : PR 2023 Jun

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Atomoxetine (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. In this study, we investigated the effect of ATX on Nav1.2 VGSC-transfected HEK293 cells with the whole-patch clamp technique. Nav1.2 VGSC current decreased by 51.15 ± 12.75% under treatment with 50 µM ATX in the resting state (holding membrane potential at - 80 mV). The IC50 of ATX against Nav1.2 VGSC current was 45.57 µM. The activation/inactivation curve of Nav1.2 VGSC currents was shifted toward hyperpolarization by 50 µM ATX. In addition, the inhibitory effect of ATX increased with membrane depolarization (holding membrane potential at - 50 mV) and its IC50 was 10.16 µM. Moreover, ATX showed the time-dependent interaction in the inactivation state. These 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. © 2023. The Author(s) under exclusive licence to Maj Institute of Pharmacology Polish Academy of Sciences.

Citation

Yoshihiko Nakatani, Kanami Ishikawa, Yuko Aoki, Takahiro Shimooki, Naoki Yamamoto, Taku Amano. Inhibitory effect of atomoxetine on Nav1.2 voltage-gated sodium channel currents. Pharmacological reports : PR. 2023 Jun;75(3):746-752