Santos A E, Duarte C B, Iizuka M, Barsoumian E L, Ham J, Lopes M C, Carvalho A P, Carvalho A L
Center for Neuroscience and Cell Biology, Department of Zoology, University of Coimbra, 3004-517 Coimbra, Portugal.
Cell Death Differ. 2006 Apr;13(4):652-60. doi: 10.1038/sj.cdd.4401785.
Cells preferentially expressing GluR4-containing alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors are particularly sensitive to excitotoxicity mediated through non-N-methyl-D-aspartate receptors. However, the excitotoxic signalling pathways associated with GluR4-containing AMPA receptors are not known. In this work, we investigated the downstream signals coupled to excitotoxicity mediated by Ca2+-permeable GluR4-containing AMPA receptors, using a HEK 293 cell line constitutively expressing the GluR4flip subunit of AMPA receptors (HEK-GluR4). Glutamate stimulation of GluR4-containing AMPA receptors decreased cell viability, in a calcium-dependent manner, when the receptor desensitisation was prevented with cyclothiazide. The excitotoxic stimulation mediated through GluR4-containing AMPA receptors increased activator protein-1 (AP-1) DNA-binding activity. Inhibition of the AP-1 activity by overexpression of a c-Jun dominant-negative form protected HEK-GluR4 cells against excitotoxic damage. Taken together, the results indicate that overactivation of Ca2+-permeable GluR4-containing AMPA receptors is coupled to a death pathway mediated, at least in part, by the AP-1 transcription factor.
优先表达含GluR4的α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体的细胞对通过非N-甲基-D-天冬氨酸受体介导的兴奋性毒性特别敏感。然而，与含GluR4的AMPA受体相关的兴奋性毒性信号通路尚不清楚。在这项研究中，我们使用组成性表达AMPA受体GluR4flip亚基的HEK 293细胞系（HEK-GluR4），研究了与Ca2+通透的含GluR4的AMPA受体介导的兴奋性毒性相关的下游信号。当用环噻嗪阻止受体脱敏时，谷氨酸对含GluR4的AMPA受体的刺激以钙依赖的方式降低细胞活力。通过含GluR4的AMPA受体介导的兴奋性毒性刺激增加了活化蛋白-1（AP-1）的DNA结合活性。通过过表达c-Jun显性负性形式抑制AP-1活性可保护HEK-GluR4细胞免受兴奋性毒性损伤。综上所述,结果表明Ca2+通透的含GluR4的AMPA受体的过度激活与至少部分由AP-1转录因子介导的死亡途径相关。
