Surface expression of GABAA receptors is transcriptionally controlled by the interplay of cAMP-response element-binding protein and its binding partner inducible cAMP early repressor
Surface expression of GABAA receptors is transcriptionally controlled by the interplay of cAMP-response element-binding protein and its binding partner inducible cAMP early repressor
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DOI：
10.1074/jbc.m705110200
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发表时间：
2008-04-04
影响因子：
4.8
通讯作者：
Russek, Shelley J.
中科院分区：
文献类型：
--
作者：
Hu, Yinghui;Lund, Ingrid V.;Russek, Shelley J.
γ-氨基丁酸（GABA）A型受体（GABA（A）R）亚单位基因的表达调控在神经元的成熟和突触发生中起着重要作用。它还与多种神经系统疾病有关。GABA（A）受体α 1亚基基因（GABRA 1）表达的变化已在癫痫、酒精滥用、戒断和应激的动物模型中报道。了解α亚基表达变化背后的遗传机制将有助于更好地理解信号转导在控制GABAAR功能中的作用，并有望为预防或治愈各种神经系统疾病提供新的治疗工具。在这里，我们表明，激活蛋白激酶C增加α 1亚基水平通过磷酸化CREB（pCREB），结合到GABRA 1启动子（GABRA 1 p）。相反，蛋白激酶A的活化降低了α 1的水平，即使在pCREB的存在下。α 1的减少依赖于诱导型cAMP早期阻遏物（ICER），这直接由ICER诱导的皮质神经元细胞表面含内源性α 1的GABA（A）Rs的下调所证明。结合蛋白激酶A刺激后神经元中含有较少α 1 γ 2的GABAARs以及内源性多巴胺受体的激活在诱导ICER后下调α 1亚基mRNA水平的事实，我们的研究确定了调节含有α 1的GABAARs的细胞表面表达的转录机制，其依赖于CREB异源二聚体的形成。
The regulated expression of type A gamma-aminobutyric acid ( GABA) receptor ( GABA(A)R) subunit genes plays a critical role in neuronal maturation and synaptogenesis. It is also associated with a variety of neurological diseases. Changes in GABA(A) receptor alpha 1 subunit gene ( GABRA1) expression have been reported in animal models of epilepsy, alcohol abuse, withdrawal, and stress. Understanding the genetic mechanism behind such changes in alpha subunit expression will lead to a better understanding of the role that signal transduction plays in control over GABAAR function and brings with it the promise of providing new therapeutic tools for the prevention or cure of a variety of neurological disorders. Here we show that activation of protein kinase C increases alpha 1 subunit levels via phosphorylation of CREB ( pCREB) that is bound to the GABRA1 promoter ( GABRA1p). In contrast, activation of protein kinase A decreases levels of alpha 1 even in the presence of pCREB. Decrease of alpha 1 is dependent upon the inducible cAMP early repressor ( ICER) as directly demonstrated by ICER-induced down-regulation of endogenous alpha 1-containing GABA(A)Rs at the cell surface of cortical neurons. Taken together with the fact that there are less alpha 1 gamma 2-containing GABAARs in neurons after protein kinase A stimulation and that activation of endogenous dopamine receptors down-regulates alpha 1 subunit mRNA levels subsequent to induction of ICER, our studies identify a transcriptional mechanism for regulating the cell surface expression of alpha 1-containing GABAARs that is dependent upon the formation of CREB heterodimers.