Neuregulin induces GABAA receptor β2 subunit expression in cultured rat cerebellar granule neurons by activating multiple signaling pathways
Neuregulin induces GABAA receptor β2 subunit expression in cultured rat cerebellar granule neurons by activating multiple signaling pathways
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DOI：
10.1111/j.1471-4159.2004.02685.x
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发表时间：
2004-09
影响因子：
4.7
通讯作者：
F. Xie;L. Raetzman;R. Siegel
中科院分区：
文献类型：
--
作者：
F. Xie;L. Raetzman;R. Siegel
GABA受体β亚单位是中枢神经系统中的主要抑制性神经递质，对γ-氨基丁酸具有敏感性。以往的研究表明，生长分化因子神经调节蛋白1选择性地诱导培养的大鼠小脑颗粒神经元表达β-2亚单位及其编码蛋白。在本报告中，我们研究了调节这一效应的信号通路。这些研究表明，NRG1对β2亚单位多肽表达的影响需要激活ErbB4受体酪氨酸激酶；其作用可被药物阻断ErbB4磷酸化或用反义寡核苷酸降低受体水平而抑制。NRG1诱导的ErbB4激活激活了丝裂原活化蛋白激酶(MAPK)、磷脂酰肌醇3-激酶(PI3K)和细胞周期蛋白依赖性激酶-5(CDK5)通路。药物阻断这些通路中的任何一个都能抑制β-2亚单位表达的增加，表明这三条通路都是介导NRG1对小脑颗粒神经元GABAA受体亚单位表达的影响所必需的。这些研究为NRG1对中枢GABAA受体表达的作用提供了新的信息。
The GABAA receptor β subunit is required to confer sensitivity to γ‐aminobutyric acid (GABA), the major inhibitory neurotransmitter in the CNS. In previous studies we demonstrated that the growth and differentiation factor neuregulin 1 (NRG1) selectively induced expression of the β2 subunit mRNA and encoded protein in rat cerebellar granule neurons in culture. In the present report we examine the signaling pathways that mediate this effect. These studies demonstrate that the effects of NRG1 on β2 subunit polypeptide expression require activation of the ErbB4 receptor tyrosine kinase; its effects are inhibited by pharmacological blockade of ErbB4 phosphorylation or reduction of receptor level with an antisense oligodeoxynucleotide. The NRG1‐induced activation of ErbB4 stimulates the mitogen‐activated protein kinase (MAPK), phosphatidylinositol 3‐kinase (PI3K) and cyclin‐dependent kinase‐5 (cdk5) pathways. Pharmacological blockade of any of these pathways inhibits increased β2 subunit expression, demonstrating that all three pathways are required to mediate the effects of NRG1 on GABAA receptor subunit expression in cerebellar granule neurons. These studies provide novel information concerning the actions of NRG1 on GABAA receptor expression in the CNS.