Safinamide, an inhibitor of monoamine oxidase, modulates the magnitude, gating, and hysteresis of sodium ion current.

IF 2.8 3区医学 Q2 PHARMACOLOGY & PHARMACY

BMC Pharmacology & Toxicology Pub Date : 2024-02-08 DOI:10.1186/s40360-024-00739-5

Te-Yu Hung, Sheng-Nan Wu, Chin-Wei Huang

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引用次数: 0

Abstract

Background: Safinamide (SAF), an α-aminoamide derivative and a selective, reversible monoamine oxidase (MAO)-B inhibitor, has both dopaminergic and nondopaminergic (glutamatergic) properties. Several studies have explored the potential of SAF against various neurological disorders; however, to what extent SAF modulates the magnitude, gating, and voltage-dependent hysteresis [Hys_(V)] of ionic currents remains unknown.

Methods: With the aid of patch-clamp technology, we investigated the effects of SAF on voltage-gated sodium ion (Na_V) channels in pituitary GH3 cells.

Results: SAF concentration-dependently stimulated the transient (peak) and late (sustained) components of voltage-gated sodium ion current (I_Na) in pituitary GH₃ cells. The conductance-voltage relationship of transient I_Na [I_Na(T)] was shifted to more negative potentials with the SAF presence; however, the steady-state inactivation curve of I_Na(T) was shifted in a rightward direction in its existence. SAF increased the decaying time constant of I_Na(T) induced by a train of depolarizing stimuli. Notably, subsequent addition of ranolazine or mirogabalin reversed the SAF-induced increase in the decaying time constant. SAF also increased the magnitude of window I_Na induced by an ascending ramp voltage V_ramp. Furthermore, SAF enhanced the Hys_(V) behavior of persistent I_Na induced by an upright isosceles-triangular V_ramp. Single-channel cell-attached recordings indicated SAF effectively increased the open-state probability of Na_V channels. Molecular docking revealed SAF interacts with both MAO and Na_V channels.

Conclusion: SAF may interact directly with Na_V channels in pituitary neuroendocrine cells, modulating membrane excitability.

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单胺氧化酶抑制剂沙芬胺能调节钠离子电流的大小、门控和滞后。

背景：萨非那胺（SAF）是一种α-氨基酰胺衍生物，也是一种选择性、可逆的单胺氧化酶（MAO）-B 抑制剂，具有多巴胺能和非多巴胺能（谷氨酸能）特性。有几项研究探讨了 SAF 治疗各种神经系统疾病的潜力；然而，SAF 在多大程度上调节离子电流的大小、门控和电压依赖性滞后 [Hys(V)]仍是未知数：方法：借助贴片钳技术，我们研究了 SAF 对垂体 GH3 细胞中电压门控钠离子（NaV）通道的影响：结果：SAF浓度依赖性地刺激了垂体GH3细胞中电压门控钠离子电流（INa）的瞬时（峰值）和晚期（持续）成分。瞬时INa[INa(T)]的电导-电压关系随SAF的存在而向更负的电位移动；然而，INa(T)的稳态失活曲线在其存在时向右移动。SAF 增加了一连串去极化刺激诱导的 INa（T）衰减时间常数。值得注意的是，随后加入雷诺嗪或米格巴林可逆转 SAF 诱导的衰减时间常数的增加。SAF 还增加了上升斜坡电压 Vramp 诱导的窗口 INa 的幅度。此外，SAF 还增强了直立等腰三角形 Vramp 诱导的持续 INa 的 Hys(V) 行为。单通道细胞连接记录表明，SAF 有效地增加了 NaV 通道的开放状态概率。分子对接显示 SAF 可与 MAO 和 NaV 通道相互作用：结论：SAF 可直接与垂体神经内分泌细胞中的 NaV 通道相互作用，从而调节膜的兴奋性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

BMC Pharmacology & Toxicology PHARMACOLOGY & PHARMACYTOXICOLOGY&nb-TOXICOLOGY

CiteScore

4.80

自引率

0.00%

发文量

审稿时长

12 weeks

期刊介绍： BMC Pharmacology and Toxicology is an open access, peer-reviewed journal that considers articles on all aspects of chemically defined therapeutic and toxic agents. The journal welcomes submissions from all fields of experimental and clinical pharmacology including clinical trials and toxicology.