Neuregulin-beta induces expression of an NMDA-receptor subunit
Neuregulin-beta induces expression of an NMDA-receptor subunit
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DOI：
10.1038/37795
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发表时间：
1997-12-25
期刊：
影响因子：
64.8
通讯作者：
Buonanno, A
中科院分区：
文献类型：
--
作者：
Ozaki, M;Sasner, M;Buonanno, A
神经调节蛋白（也称为ARLA， NDF, heregulin， GGF）是一个广泛表达的生长和分化因子家族。由运动神经元分泌的神经调节蛋白在成熟的神经肌肉连接处积累，在那里它们刺激编码特定乙酰胆碱受体的基因的转录。然而，这些因子如何在中枢突触起作用尚不清楚。在成熟的小脑中，神经调节蛋白集中在支配内部颗粒细胞层颗粒细胞的谷氨酸能杂乱纤维中(1)。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）受体基因表达的影响，因为在突触形成过程中，受体NR2C亚基的表达在神经元内颗粒细胞层中被特异性诱导，受体组成发生了巨大变化。在这里，我们报告了在培养的小脑切片中添加神经调节蛋白- β亚型特异性地增加NR2C信使rna的表达至少100倍；神经调节蛋白- α亚型的影响很小。这种对NR2C表达的刺激需要NMDA受体和神经调节蛋白β的突触活性。nmda受体通道阻断剂AP-5的加入可以阻止神经调节蛋白上调NR2C亚基，而AMPA/ kain酸受体拮抗剂则没有作用。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NR2C亚基之前表达其受体ErbB2和ErbB4。我们的研究结果表明，神经调节蛋白以一种类似于神经肌肉连接的方式调节大脑成熟突触中神经递质受体的组成。
Neuregulins (also known as ARLA, 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 messy fibres that innervate granule cells in the internal granule-cell layer(1). 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.