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BIG1, a Brefeldin A-Inhibited Guanine Nucleotide-Exchange Factor, Is Required for GABA-Gated Cl-/sup> Influx Through Regulation of GABAA Receptor Trafficking
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  • 作者:Cuixian Li (1)
    Shaorui Chen (1)
    Yang Yu (1)
    Chun Zhou (1)
    Ying Wang (1)
    Kang Le (1)
    Dong Li (1)
    Weiwei Shao (1)
    Liang Lu (1)
    Yan You (1)
    Jin Peng (1)
    Heqing Huang (1)
    Peiqing Liu (1)
    Xiaoyan Shen (1) (2)
  • 关键词:GABAA receptors ; BIG1 ; Trafficking ; Chloride ions influx ; GEF activity
  • 刊名:Molecular Neurobiology
  • 出版年:2014
  • 出版时间:April 2014
  • 年:2014
  • 卷:49
  • 期:2
  • 页码:808-819
  • 全文大小:6,487 KB
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  • 作者单位:Cuixian Li (1)
    Shaorui Chen (1)
    Yang Yu (1)
    Chun Zhou (1)
    Ying Wang (1)
    Kang Le (1)
    Dong Li (1)
    Weiwei Shao (1)
    Liang Lu (1)
    Yan You (1)
    Jin Peng (1)
    Heqing Huang (1)
    Peiqing Liu (1)
    Xiaoyan Shen (1) (2)

    1. Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, No. 132, Waihuan East Road, Higher Education Mega Center, Guangzhou, 510006, People’s Republic of China
    2. Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, People’s Republic of China
  • ISSN:1559-1182
文摘
GABAA receptors (GABAARs) mediate the majority of fast synaptic inhibition. Trafficking regulation and protein–protein interactions that maintain the appropriate number of GABAARs at the cell surface are considered to be important mechanisms for controlling the strength of synaptic inhibition. Here, we report that BIG1, a brefeldin A (BFA)-inhibited guanine nucleotide-exchange factor (GEF) which has a known role in vesicle trafficking, is a new binding partner of GABAARs. Treatment of neurons with BFA, an uncompetitive inhibitor of BIG1 GEF activity, or depletion of BIG1 by small RNA interference (siRNA) significantly decreased GABAARs at the neuronal surface and suppressed GABA-gated influx of chloride ions. Over-expression of HA-tagged BIG1-E793K, a dominant-negative mutant, also significantly decreased GABAARs at the neuronal surface, but had no effect on the total amount of GABAARs. Inhibition of GABAAR endocytosis by muscimol increased both GABAARs and BIG1 at the neuronal surface in a time-dependent fashion, and this increase could be abolished by bicuculline. Finally, depletion of BIG1 by siRNA inhibited the muscimol-stimulated increase of GABAARs. Those data suggest an important function of BIG1 in trafficking of GABAARs to the cell surface through its GEF activity. Thus, we identify an important role of BIG1 in modulating GABA-gated Cl?/sup> influx through the regulation of cell surface expression of GABAARs.

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