Ozaki M, Sasner M, Yano R, Lu H S, Buonanno A
Unit on Molecular Neurobiology, National Institutes of Health, Bethesda, Maryland 20892-4480, USA.
Nature. 1997;390(6661):691-4. doi: 10.1038/37795.
Neuregulins (also known as ARIA, NDF, heregulin, GGF) are a family of widely expressed growth and differentiation factors. Neuregulins secreted from motor neurons accumulate at maturing neuromuscular junctions, where they stimulate transcription of genes encoding specific acetylcholine receptors. How these factors function at central synapses, however, is unknown. In the maturing cerebellum, neuregulins are concentrated in glutamatergic mossy fibres that innervate granule cells in the internal granule-cell layer. We have analysed the effects of neuregulins on the expression of genes encoding NMDA (N-methyl-D-aspartate) receptors in the cerebellum, because receptor composition changes dramatically as expression of the receptor NR2C subunit is specifically induced in neurons in the internal granule-cell layer during synaptogenesis. Here we report that addition of a neuregulin-beta isoform to cultured cerebellar slices specifically increases the expression of NR2C messenger RNAs by at least 100-fold; effects are only minor with a neuregulin-alpha isoform. This stimulation of NR2C expression requires synaptic activity by NMDA receptors, as well as neuregulin-beta. Addition of the NMDA-receptor-channel blocker AP-5 prevents upregulation of the NR2C subunit by neuregulin, whereas an AMPA/kainate-receptor antagonist does not. Consistent with these effects of neuregulin, we find that granule cells express its receptors ErbB2 and ErbB4 before the NR2C subunit of the NMDA receptor. Our results indicate that neuregulins regulate the composition of neurotransmitter receptors in maturing synapses in the brain, in a manner analogous to the neuromuscular junction.
神经调节蛋白（也称为ARIA、NDF、神经调节素、胶质生长因子）是一类广泛表达的生长和分化因子。运动神经元分泌的神经调节蛋白在成熟的神经肌肉接头处聚集，在那里它们刺激编码特定乙酰胆碱受体的基因转录。然而，这些因子在中枢突触中如何发挥作用尚不清楚。在成熟的小脑中，神经调节蛋白集中在支配内颗粒层颗粒细胞的谷氨酸能苔藓纤维中。我们分析了神经调节蛋白对小脑中编码NMDA（N-甲基-D-天冬氨酸）受体的基因表达的影响，因为在突触形成过程中，内颗粒层神经元中受体NR2C亚基的表达被特异性诱导时，受体组成会发生显著变化。在此我们报告，向培养的小脑切片中添加神经调节蛋白β亚型可使NR2C信使核糖核酸的表达特异性增加至少100倍；而神经调节蛋白α亚型的作用较小。这种对NR2C表达的刺激需要NMDA受体的突触活动以及神经调节蛋白β。添加NMDA受体通道阻滞剂AP-5可阻止神经调节蛋白对NR2C亚基的上调，而AMPA/海人藻酸受体拮抗剂则无此作用。与神经调节蛋白的这些作用一致，我们发现颗粒细胞在NMDA受体的NR2C亚基之前表达其受体ErbB2和ErbB4。我们的结果表明，神经调节蛋白以类似于神经肌肉接头处的方式调节大脑中成熟突触中神经递质受体的组成。
