Glutamate and GABAA receptor crosstalk mediates homeostatic regulation of neuronal excitation in the mammalian brain

doi:10.1038/s41392-022-01148-y

	Glutamate and GABAA receptor crosstalk mediates homeostatic regulation of neuronal excitation in the mammalian brain
	Wen, Ya 1; Dong, Zhifang 2; Liu, Jun 1; Axerio-Cilies, Peter 1; Du, Yehong 2; Li, Junjie 2; Chen, Long 2; Zhang, Lu 2; Liu, Lidong 1; Lu, Jie 1; Zhou, Ning3 ; Chuan Wu, Dong 1; Wang, Yu Tian 1
	2022-10-03
发表期刊	SIGNAL TRANSDUCTION AND TARGETED THERAPY
ISSN	2095-9907
EISSN	2059-3635
卷号	7 期号:1
发表状态	已发表
DOI	10.1038/s41392-022-01148-y
摘要	Maintaining a proper balance between the glutamate receptor-mediated neuronal excitation and the A type of GABA receptor (GABAR) mediated inhibition is essential for brain functioning; and its imbalance contributes to the pathogenesis of many brain disorders including neurodegenerative diseases and mental illnesses. Here we identify a novel glutamate-GABAR interaction mediated by a direct glutamate binding of the GABAR. In HEK293 cells overexpressing recombinant GABARs, glutamate and its analog ligands, while producing no current on their own, potentiate GABA-evoked currents. This potentiation is mediated by a direct binding at a novel glutamate binding pocket located at the α/β subunit interface of the GABAR. Moreover, the potentiation does not require the presence of a γ subunit, and in fact, the presence of γ subunit significantly reduces the potency of the glutamate potentiation. In addition, the glutamate-mediated allosteric potentiation occurs on native GABARs in rat neurons maintained in culture, as evidenced by the potentiation of GABAR-mediated inhibitory postsynaptic currents and tonic currents. Most importantly, we found that genetic impairment of this glutamate potentiation in knock-in mice resulted in phenotypes of increased neuronal excitability, including decreased thresholds to noxious stimuli and increased seizure susceptibility. These results demonstrate a novel cross-talk between excitatory transmitter glutamate and inhibitory GABAR. Such a rapid and short feedback loop between the two principal excitatory and inhibitory neurotransmission systems may play a critical homeostatic role in fine-tuning the excitation-inhibition balance (E/I balance), thereby maintaining neuronal excitability in the mammalian brain under both physiological and pathological conditions.
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收录类别	SCIE
语种	英语
Scopus 记录号	2-s2.0-85139171007
来源库	Scopus
引用统计
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/238178
专题	iHuman研究所_PI研究组_周宁组
通讯作者	Wang, Yu Tian
作者单位	1.DM Centre for Brain Health and Department of Medicine,Vancouver Coastal Health Research Institute,University of British Columbia,Vancouver,V6T 2B5,Canada 2.Pediatric Research Institute,Ministry of Education Key Laboratory of Child Development and Disorders,National Clinical Research Center for Child Health and Disorders,China International Science and Technology Cooperation Base of Child Development and Critical Disorders,Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders,Children’s Hospital of Chongqing Medical University,Chongqing,400014,China 3.iHuman Institue,ShanghaiTech University,Shanghai,China
推荐引用方式 GB/T 7714	Wen, Ya,Dong, Zhifang,Liu, Jun,et al. Glutamate and GABAA receptor crosstalk mediates homeostatic regulation of neuronal excitation in the mammalian brain[J]. SIGNAL TRANSDUCTION AND TARGETED THERAPY,2022,7(1).
APA	Wen, Ya.,Dong, Zhifang.,Liu, Jun.,Axerio-Cilies, Peter.,Du, Yehong.,...&Wang, Yu Tian.(2022).Glutamate and GABAA receptor crosstalk mediates homeostatic regulation of neuronal excitation in the mammalian brain.SIGNAL TRANSDUCTION AND TARGETED THERAPY,7(1).
MLA	Wen, Ya,et al."Glutamate and GABAA receptor crosstalk mediates homeostatic regulation of neuronal excitation in the mammalian brain".SIGNAL TRANSDUCTION AND TARGETED THERAPY 7.1(2022).