Department of Pharmacotherapeutics, School of Pharmacy, International University of Health and Welfare, 2600-1 Kitakanemaru, Ohtawara, Tochigi, 324-8501, Japan.
Center for Basic Medical Research, International University of Health and Welfare, 2600-1 Kitakanemaru, Ohtawara, Tochigi, 324-8501, Japan.
Pharmacol Rep. 2023 Jun;75(3):746-752. doi: 10.1007/s43440-023-00477-1. Epub 2023 Mar 14.
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 IC 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 IC 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.
阿托西汀（ATX）是一种去甲肾上腺素再摄取抑制剂（NRI），通过增加突触间隙神经递质浓度来减轻注意力缺陷多动障碍（AD/HD）的症状。尽管 Nav1.2 电压门控钠离子通道（VGSCs）被认为在突触连接处单胺递质释放中起作用，但 ATX 如何影响 Nav1.2 VGSCs 尚不清楚。
本研究采用全膜片钳技术研究 ATX 对 Nav1.2 VGSC 转染 HEK293 细胞的影响。
在静息状态（保持膜电位在-80 mV）下，50 µM ATX 处理可使 Nav1.2 VGSC 电流减少 51.15±12.75%。ATX 对 Nav1.2 VGSC 电流的 IC 为 45.57 µM。50 µM ATX 使 Nav1.2 VGSC 电流的激活/失活曲线向超极化方向移动。此外，ATX 的抑制作用随膜去极化而增加（保持膜电位在-50 mV），其 IC 为 10.16 µM。此外，ATX 在失活状态下表现出时间依赖性相互作用。
这些发现表明 ATX 与 Nav1.2 VGSCs 相互作用，以产生电流抑制和状态依赖性动力学特性的修饰。
