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首页 » J Neurosci.:神经系统退行性疾病潜在靶点——GABA(B)R

J Neurosci.:神经系统退行性疾病潜在靶点——GABA(B)R

来源:生物通 2010-04-15 00:27

γ-氨基丁酸(GABA)是中枢神经系统中的主要抑制性神经递质。从突触上释放出来的GABA通过作用于突触后膜上的γ-氨基丁酸受体而对细胞的行为与生理活动进行调节。该受体包括GABA门控离子通道型受体(GABAAR和GABACR)和Gi/o偶联的代谢型γ-氨基丁酸B型受体(GABABR)。

华中科技大学分子生物物理教育部重点实验室刘剑峰教授领衔的研究小组在神经细胞凋亡机制研究方面取得新的进展,相关成果文章公布在最近的《神经科学杂志》(Journal  of  Neuroscience)上。

研究表明多种神经系统退行性疾病(如癫痫、精神分裂症、亨庭顿症等)和精神疾病(如焦虑症与抑郁症等)均与在神经系统广泛表达的GABABR的功能紊乱密切相关。因此,GABABR成了多种神经系统疾病和精神疾病治疗的药物靶点。

刘剑峰教授研究组发现GABABR的特异性激活后,通过转激活受体酪氨酸激酶,  胰岛素样生长因子1受体(IGF-1R)保护神经元凋亡。进一步的深入研究表明,Gi/o蛋白,PLC,细胞内钙离子信号,和黏着斑激酶(FAK1)调节着GABABR与IGF-1R之间的相互作用(crosstalk),被GABABR转激活的IGF-1R进而诱导下游的Src激酶,PI3激酶和Akt信号的激活。这些研究不仅阐明了GABABR的一种新的生理功能,并对深入揭示了GPCR与RTK之间的协同作用在细胞间相互通信过程中起着重要的作用与生理意义。而且提示了GABABR可以作为相关神经系统退行性疾病治疗的新的潜在药物靶点。

参与研究的有华中科技大学分子生物物理教育部重点实验室中法联合药物筛选中心的博士研究生涂海军,许婵娟等。(生物谷Bioon.com)

生物谷推荐原文出处:

The Journal of Neuroscience  doi:10.1523/JNEUROSCI.2343-09.2010

GABAB receptor activation protects neurons from apoptosis via IGF-1 receptor transactivation.
Haijun Tu,1 * Chanjuan Xu,1 * Wenhua Zhang,1 Qiuyao Liu,1 Philippe Rondard,2 Jean-Philippe Pin,2 and Jianfeng Liu1

1Sino-France Laboratory for Drug Screening, Key Laboratory of Molecular Biophysics of Ministry of Education, School of Life Science and Technology, Huazhong University of Science and Technology, 430074 Wuhan, Hubei, China, and 2Centre National de la Recherche Scientifique, UMR5203, Institut de Génomique Fonctionnelle, Inserm, U661 and Université Montpellier 1, 2, Montpellier F-34000, France

The G-protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs) play key roles in cell–cell communication. Several studies revealed important synergisms between these two types of receptors, with some of the actions of either receptor being mediated through transactivation of the other. Among the large GPCR family, GABAB receptor is activated by the neurotransmitter GABA, and is expressed in most neurons where it mediates slow and prolonged inhibition of synaptic transmission. Here we show that this receptor is involved in the regulation of life and death decisions of cerebellar granule neurons (CGNs). We show that specific activation of GABAB receptor can protect neurons from apoptosis through a mechanism that involves transactivation of the IGF-1 receptor (IGF-1R). Further work demonstrated that this cross talk was dependent on Gi/o-protein, PLC, cytosolic Ca2+, and FAK1 but independent of PKC, while IGF-1R-induced signaling involved Src kinase, PI3 kinase, and Akt activation. These results reveal a new function for this important GPCR and further highlight the importance of functional cross-talk networks between GPCRs and RTKs. Our results reveal GABAB receptor as a potential drug target for the treatment of neurodegenerative disorders.

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