Institute of Molecular and Clinical Immunology, Otto von Guericke University Magdeburg, Magdeburg, Germany.
Mol Cell Biol. 2014 Mar;34(5):820-31. doi: 10.1128/MCB.01273-13. Epub 2013 Dec 16.
N-methyl-D-aspartate receptors (NMDARs) are ligand-gated ion channels that play an important role in neuronal development, plasticity, and excitotoxicity. NMDAR antagonists are neuroprotective in animal models of neuronal diseases, and the NMDAR open-channel blocker memantine is used to treat Alzheimer's disease. In view of the clinical application of these pharmaceuticals and the reported expression of NMDARs in immune cells, we analyzed the drug's effects on T-cell function. NMDAR antagonists inhibited antigen-specific T-cell proliferation and cytotoxicity of T cells and the migration of the cells toward chemokines. These activities correlated with a reduction in T-cell receptor (TCR)-induced Ca(2+) mobilization and nuclear localization of NFATc1, and they attenuated the activation of Erk1/2 and Akt. In the presence of antagonists, Th1 effector cells produced less interleukin-2 (IL-2) and gamma interferon (IFN-γ), whereas Th2 cells produced more IL-10 and IL-13. However, in NMDAR knockout mice, the presumptive expression of functional NMDARs in wild-type T cells was inconclusive. Instead, inhibition of NMDAR antagonists on the conductivity of Kv1.3 and KCa3.1 potassium channels was found. Hence, NMDAR antagonists are potent immunosuppressants with therapeutic potential in the treatment of immune diseases, but their effects on T cells have to be considered in that Kv1.3 and KCa3.1 channels are their major effectors.
N-甲基-D-天冬氨酸受体（NMDARs）是配体门控离子通道，在神经元发育、可塑性和兴奋性毒性中发挥重要作用。NMDAR 拮抗剂在神经元疾病的动物模型中具有神经保护作用，NMDAR 开放通道阻滞剂美金刚被用于治疗阿尔茨海默病。鉴于这些药物的临床应用以及免疫细胞中报道的 NMDAR 表达，我们分析了药物对 T 细胞功能的影响。NMDAR 拮抗剂抑制抗原特异性 T 细胞增殖和 T 细胞的细胞毒性以及细胞向趋化因子的迁移。这些活性与 T 细胞受体（TCR）诱导的 Ca(2+)动员和 NFATc1 的核定位减少相关，并且它们减弱了 Erk1/2 和 Akt 的激活。在拮抗剂存在的情况下，Th1 效应细胞产生较少的白细胞介素-2 (IL-2)和γ干扰素 (IFN-γ)，而 Th2 细胞产生更多的 IL-10 和 IL-13。然而，在 NMDAR 敲除小鼠中，野生型 T 细胞中假定表达功能性 NMDARs 的情况并不明确。相反，发现 NMDAR 拮抗剂对 Kv1.3 和 KCa3.1 钾通道的电导率具有抑制作用。因此，NMDAR 拮抗剂是具有治疗潜力的免疫抑制剂，可用于治疗免疫疾病，但必须考虑它们对 T 细胞的影响，因为 Kv1.3 和 KCa3.1 通道是它们的主要效应器。
