Bernard A, Ferhat L, Dessi F, Charton G, Represa A, Ben-Ari Y, Khrestchatisky M
Université René Descartes Paris V, INSERM Unité 29, Paris, France.
Eur J Neurosci. 1999 Feb;11(2):604-16. doi: 10.1046/j.1460-9568.1999.00479.x.
Kainate (KA) is a potent neuroexcitatory agent in several areas of the adult brain, with convulsant and excitotoxic properties that increase as ontogeny proceeds. Besides its depolarizing actions, KA may enhance intracellular accumulation of Ca2+ to promote selective neuronal damage. The effects of KA are mediated by specific receptors recently considered to be involved in fast neurotransmission and that can be activated synaptically. KA receptors, e.g. GluR5 and GluR6 have been characterized by molecular cloning. Structure-function relationships indicate that in the MII domain of these KA receptors, a glutamine (Q) or arginine (R) residue determines ion selectivity. The arginine stems from post-transcriptional editing of the GluR5 and GluR6 pre-RNAs, and the unedited and edited versions of GluR6 elicit distinct Ca2+ permeability. Using a PCR-based approach, we show that in vivo, Q/R editing in the GluR5 and GluR6 mRNAs is modulated during ontogeny and differs substantially in a variety of nervous tissues. GluR5 editing is highest in peripheral nervous tissue, e.g. the dorsal root ganglia, where GluR6 expression is barely detectable. In contrast, GluR6 editing is maximal in forebrain and cerebellar structures where GluR5 editing is lower. Intra-amygdaloid injections of KA provide a model of temporal lobe epilepsy, and we show that following seizures, the extent of GluR5 and GluR6 editing is altered in the hippocampus. However, in vitro, high levels of glutamate and potassium-induced depolarizations have no effect on GluR5 and GluR6 Q/R editing. GluR6 editing is rapidly enhanced to maximal levels in primary cultures of cerebellar granule neurons but not in cultured hippocampal pyramidal neurons. Finally, we show that cultured glial cells express partially edited GluR6 mRNAs. Our results indicate that Q/R editing of GluR5 and GluR6 mRNAs is structure-, cell type- and time-dependent, and suggest that editing of these mRNAs is not co-regulated.
海人酸（KA）在成人大脑的多个区域是一种强效神经兴奋剂，具有惊厥和兴奋毒性特性，且随着个体发育进程而增强。除了其去极化作用外，KA可能会增强细胞内Ca2+的积累，从而促进选择性神经元损伤。KA的作用是由最近被认为参与快速神经传递且可通过突触激活的特定受体介导的。KA受体，如GluR5和GluR6，已通过分子克隆进行了表征。结构-功能关系表明，在这些KA受体的MII结构域中，谷氨酰胺（Q）或精氨酸（R）残基决定离子选择性。精氨酸源自GluR5和GluR6前体RNA的转录后编辑，未编辑和编辑后的GluR6版本具有不同的Ca2+通透性。使用基于PCR的方法，我们表明在体内，GluR5和GluR6 mRNA中的Q/R编辑在个体发育过程中受到调节，并且在各种神经组织中存在显著差异。GluR5编辑在外周神经组织中最高，例如背根神经节，而在那里几乎检测不到GluR6的表达。相反，GluR6编辑在前脑和小脑结构中最大，而GluR5编辑较低。杏仁核内注射KA可提供颞叶癫痫模型，我们表明癫痫发作后，海马体中GluR5和GluR6编辑的程度会发生改变。然而，在体外，高浓度的谷氨酸和钾诱导的去极化对GluR5和GluR6的Q/R编辑没有影响。GluR6编辑在小脑颗粒神经元的原代培养物中迅速增强至最大水平，但在培养的海马锥体神经元中则不然。最后，我们表明培养的胶质细胞表达部分编辑的GluR6 mRNA。我们的结果表明，GluR5和GluR6 mRNA的Q/R编辑是结构、细胞类型和时间依赖性的，并表明这些mRNA的编辑不是共同调节的。
