decynium-22 通过抑制离子通道来损害胞吐递质释放,Frontiers in Pharmacology

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decynium-22 通过抑制离子通道来损害胞吐递质释放
Frontiers in Pharmacology ( IF 4.4 ) Pub Date : 2023-10-10 , DOI: 10.3389/fphar.2023.1276100
Gabriele Haar ₁ , Katsiaryna Hrachova ₁ , Tanja Wagner ₁ , Stefan Boehm ₁ , Klaus Schicker ₁

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简介：除了娜家族的成员+/氯-依赖性单胺转运蛋白、有机阳离子转运蛋白（OCT），特别是 OCT3，以及质膜单胺转运蛋白（PMAT）可能有助于神经元对相应神经递质的再摄取。与众多的单胺转运蛋白阻断剂相反，只有非常有限的 OCT3 和 PMAT 特异性阻断剂可用。事实上，decynium-22 是唯一对两种转运蛋白均具有微摩尔亲和力的阻断剂，该分子经常用于确定 OCT3 和/或 PMAT 分别作为抗抑郁药物和精神兴奋剂靶标的作用。方法/结果：测试对于这些转运蛋白在交感神经系统中的功能，[3H]1-甲基-4-苯基吡啶鎓 (MPP) 的摄取和释放+）在大鼠颈上神经节的原代培养物中进行了研究。去甲肾上腺素转运蛋白阻断剂可卡因或地昔帕明的摄取量减少约 70%，OCT3 阻断剂皮质酮或 β-雌二醇的摄取量减少约 30%；decynium-22 在 3 μM 时实现了完全吸收抑制，最大效果减半。皮质酮或β-雌二醇可增强去极化依赖性释放，但癸鎓-22 可减少去极化依赖性释放。由于后一种效应不太可能与 OCT3 和/或 PMAT 的作用相关，因此进行电生理记录表明，decynium-22 抑制颈上神经节神经元中电压激活的钙通道的动作电位放电和电流。讨论：这些结果表明decynium-22 可以通过干扰几种类型的离子通道来损害胞吐神经递质的释放。在解释使用 decynium-22 作为通过 OCT3 和/或 PMAT 的递质再摄取的原型抑制剂获得的结果时，需要考虑 decynium-22 的这种转运蛋白独立效应，它会干扰基本神经元功能。

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Impairment of exocytotic transmitter release by decynium-22 through an inhibition of ion channels

Introduction: In addition to members of the family of Na+/Cl− dependent monoamine transporters, organic cation transporters (OCTs), in particular OCT3, as well as the plasma membrane monoamine transporter (PMAT) may contribute to neuronal reuptake of according neurotransmitters. As opposed to the numerous blockers of monoamine transporters, only a very limited number of specific blockers of OCT3 and PMAT are available. In fact, decynium-22 is the only blocking agent with micromolar affinities for both transport proteins, and this molecule is frequently used to establish roles of OCT3 and/or PMAT as targets for antidepressant drugs and psychostimulants, respectively.Methods/Results: To test for a function of these transporters in the sympathetic nervous system, uptake and release of [3H]1-methyl-4-phenylpyridinium (MPP+) was investigated in primary cultures of rat superior cervical ganglia. Uptake was reduced by cocaine or desipramine, blockers of the noradrenaline transporter, by about 70% and by corticosterone or β-estradiol, blockers of OCT3, by about 30%; decynium-22 achieved complete inhibition of uptake with half maximal effects at 3 μM. Depolarization dependent release was enhanced by corticosterone or β-estradiol, but reduced by decynium-22. As the latter effect is unlikely to be related to actions at OCT3 and/or PMAT, electrophysiological recordings were performed to reveal that decynium-22 inhibits action potential firing and currents through voltage activated calcium channels in superior cervical ganglion neurons.Discussion: These results demonstrate that decynium-22 can impair exocytotic neurotransmitter release by interfering with several types of ion channels. Such transporter-independent effects of decynium-22 that my interfere with basic neuronal functions need to be considered when interpreting results obtained with decynium-22 as prototypic inhibitor of transmitter reuptake via OCT3 and/or PMAT.

更新日期：2023-10-10

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