Mahajan S S, Ziff E B
The Department of Biochemistry, New York University School of Medicine, 550 First Avenue, New York, NY 1006, USA.
Mol Cell Neurosci. 2007 Jul;35(3):470-81. doi: 10.1016/j.mcn.2007.04.006. Epub 2007 May 4.
RNA editing modifies the GluR2 AMPA receptor subunit pore loop at the Q/R site and limits receptor Ca(2+) permeability. Editing failure is implicated in neurodegenerative diseases, including amyotrophic lateral sclerosis. We show that channels with unedited GluR2 are highly toxic in cultured hippocampal neurons. Toxicity exceeds that of other Ca(2+)-permeable AMPA receptor types and is influenced by agonist binding site mutations, ability to desensitize, and extracellular Ca(2+) levels. Significantly, toxicity also depends on GluR2's constitutive surface trafficking, a function dependent on GluR2 C-terminal domain interaction with NSF, a specialized chaperone. We have exploited the interaction between unedited GluR2 and NSF to reduce GluR2 surface levels. We show that a peptide that blocks the GluR2-NSF interaction reduces unedited GluR2 toxicity by reducing receptor surface expression. Peptide block of trafficking provides a model for design of drugs to reduce unedited GluR2 excitotoxicity in neurodegenerative diseases that result from editing failure.
RNA编辑在Q/R位点修饰了谷氨酸受体2（GluR2）α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体亚基的孔环，并限制了受体对钙离子（Ca(2+)）的通透性。编辑失败与包括肌萎缩侧索硬化症在内的神经退行性疾病有关。我们发现，带有未编辑GluR2的通道在培养的海马神经元中具有高度毒性。其毒性超过了其他钙离子通透型AMPA受体类型，并且受激动剂结合位点突变、脱敏能力和细胞外钙离子水平的影响。重要的是，毒性还取决于GluR2的组成型表面转运，这一功能依赖于GluR2的C末端结构域与一种特殊伴侣蛋白N-乙基马来酰亚胺敏感因子（NSF）的相互作用。我们利用未编辑的GluR2与NSF之间的相互作用来降低GluR2的表面水平。我们发现，一种阻断GluR2-NSF相互作用的肽通过降低受体表面表达来降低未编辑GluR2的毒性。对转运的肽阻断为设计药物提供了一个模型，以降低因编辑失败导致的神经退行性疾病中未编辑GluR2的兴奋性毒性。
