Department of Anesthesiology, Far-Eastern Memorial Hospital, New Taipei, Taiwan.
J Pharmacol Exp Ther. 2012 May;341(2):532-42. doi: 10.1124/jpet.111.191189. Epub 2012 Feb 22.
σ-1 Receptors are expressed in the brain, and their activation has been shown to prevent neuronal death associated with glutamate toxicity. This study investigates the possible mechanism and effect of [2S-(2α,6α,11R*]-1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(2-propenyl)-2,6-methano-3-benzazocin-8-ol (SKF10047), a σ-1 receptor agonist, on endogenous glutamate release in the nerve terminals of rat cerebral cortex. Results show that SKF10047 inhibited the release of glutamate evoked by the K⁺ channel blocker 4-aminopyridine (4-AP), and the σ-1 receptor antagonist N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine (BD1047) blocked this phenomenon. The effects of SKF10047 on the evoked glutamate release were prevented by the chelating extracellular Ca²⁺ions and the vesicular transporter inhibitor bafilomycin A1. However, the glutamate transporter inhibitor DL-threo-β-benzyl-oxyaspartate did not have any effect on the action of SKF10047. SKF10047 decreased the depolarization-induced increase in the cytosolic free Ca²⁺ concentration (Ca²⁺), but did not alter 4-AP-mediated depolarization. Furthermore, the effects of SKF10047 on evoked glutamate release were prevented by blocking the Ca(v)2.2 (N-type) and Ca(v)2.1 (P/Q-type) channels, but not by blocking the ryanodine receptors or the mitochondrial Na⁺/Ca²⁺ exchange. In addition, conventional protein kinase C (PKC) inhibitors abolished the SKF10047 effect on 4-AP-evoked glutamate release. Western blot analyses showed that SKF10047 decreased the 4-AP-induced phosphorylation of PKC and PKCα. These results show that σ-1 receptor activation inhibits glutamate release from rat cortical nerve terminals. This effect is linked to a decrease in Ca²⁺ caused by Ca²⁺ entry through presynaptic voltage-dependent Ca²⁺ channels and the suppression of the PKC signaling cascade.
σ-1 受体在大脑中表达，其激活已被证明可防止与谷氨酸毒性相关的神经元死亡。本研究探讨了 σ-1 受体激动剂 [2S-(2α,6α,11R*]-1,2,3,4,5,6-六氢-6,11-二甲基-3-(2-丙烯基)-2,6-甲撑-3-苯并氮杂环辛-8-醇（SKF10047）对大鼠大脑皮质神经末梢内源性谷氨酸释放的可能机制和作用。结果表明，SKF10047 抑制了 K⁺通道阻断剂 4-氨基吡啶（4-AP）诱发的谷氨酸释放，而 σ-1 受体拮抗剂 N-[2-(3,4-二氯苯基)乙基]-N-甲基-2-(二甲氨基)乙胺（BD1047）阻断了这一现象。螯合细胞外 Ca²⁺离子和囊泡转运抑制剂巴弗洛霉素 A1 可阻止 SKF10047 对诱发谷氨酸释放的作用。然而，谷氨酸转运体抑制剂 DL-threo-β-苄基-氧基天冬氨酸对 SKF10047 的作用没有任何影响。SKF10047 降低了去极化诱导的细胞浆游离 Ca²⁺浓度 (Ca²⁺)增加，但不改变 4-AP 介导的去极化。此外，SKF10047 对诱发谷氨酸释放的作用可通过阻断 Ca(v)2.2（N 型）和 Ca(v)2.1（P/Q 型）通道而被阻断，但不能通过阻断肌浆网 Ca²⁺释放通道或线粒体 Na⁺/Ca²⁺交换而被阻断。此外，传统的蛋白激酶 C（PKC）抑制剂消除了 SKF10047 对 4-AP 诱发谷氨酸释放的作用。Western blot 分析表明，SKF10047 降低了 4-AP 诱导的 PKC 和 PKCα磷酸化。这些结果表明，σ-1 受体的激活抑制了大鼠皮质神经末梢的谷氨酸释放。这种作用与通过突触前电压依赖性 Ca²⁺通道进入 Ca²⁺引起的 Ca²⁺减少以及抑制 PKC 信号级联有关。
