Department of Pediatrics, Chi-Mei Medical Center, Tainan, Taiwan.
Department of Physiology, National Cheng Kung University Medical College, Tainan, Taiwan.
BMC Pharmacol Toxicol. 2024 Feb 8;25(1):17. doi: 10.1186/s40360-024-00739-5.
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] of ionic currents remains unknown.
With the aid of patch-clamp technology, we investigated the effects of SAF on voltage-gated sodium ion (Na) channels in pituitary GH3 cells.
SAF concentration-dependently stimulated the transient (peak) and late (sustained) components of voltage-gated sodium ion current (I) in pituitary GH cells. The conductance-voltage relationship of transient I [I] was shifted to more negative potentials with the SAF presence; however, the steady-state inactivation curve of I was shifted in a rightward direction in its existence. SAF increased the decaying time constant of I 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 induced by an ascending ramp voltage V. Furthermore, SAF enhanced the Hys behavior of persistent I induced by an upright isosceles-triangular V. Single-channel cell-attached recordings indicated SAF effectively increased the open-state probability of Na channels. Molecular docking revealed SAF interacts with both MAO and Na channels.
SAF may interact directly with Na channels in pituitary neuroendocrine cells, modulating membrane excitability.
沙芬酰胺（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。几项研究探索了 SAF 对各种神经疾病的潜在作用；然而，SAF 调节离子电流幅度、门控和电压依赖性滞后 [Hys] 的程度仍不清楚。
借助膜片钳技术，我们研究了 SAF 对垂体 GH3 细胞中电压门控钠离子（Na）通道的影响。
SAF 浓度依赖性地刺激了垂体 GH 细胞中电压门控钠离子电流（I）的瞬态（峰值）和晚期（持续）成分。SAF 存在时，瞬态 I [I]的电导-电压关系向更负的电位移动；然而，I 的稳态失活曲线在其存在下向右侧移动。SAF 增加了由去极化刺激串引起的 I 的衰减时间常数。值得注意的是，随后加入雷诺嗪或米罗加巴林可逆转 SAF 诱导的衰减时间常数增加。SAF 还增加了上升斜坡电压 V 诱导的窗口 I 的幅度。此外，SAF 增强了直立等腰三角形 V 诱导的持续 I 的 Hys 行为。单通道细胞附着记录表明 SAF 有效增加了 Na 通道的开放状态概率。分子对接显示 SAF 与 MAO 和 Na 通道都相互作用。
SAF 可能直接与垂体神经内分泌细胞中的 Na 通道相互作用，调节膜兴奋性。
