Structural basis of GABARAP-mediated GABAA receptor trafficking and functions on GABAergic synaptic transmission

Jin Ye, Guichang Zou, Ruichi Zhu, Chao Kong, Chenjian Miao, Mingjie Zhang, Jianchao Li (), Wei Xiong () and Chao Wang ()
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Jin Ye: University of Science and Technology of China
Guichang Zou: University of Science and Technology of China
Ruichi Zhu: Hong Kong University of Science and Technology, Clear Water Bay, Kowloon
Chao Kong: University of Science and Technology of China
Chenjian Miao: University of Science and Technology of China
Mingjie Zhang: Hong Kong University of Science and Technology, Clear Water Bay, Kowloon
Jianchao Li: South China University of Technology
Wei Xiong: University of Science and Technology of China
Chao Wang: University of Science and Technology of China

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: Abstract GABAA receptors (GABAARs) are the primary fast inhibitory ion channels in the central nervous system. Dysfunction of trafficking and localization of GABAARs to cell membranes is clinically associated with severe psychiatric disorders in humans. The GABARAP protein is known to support the stability of GABAARs in synapses, but the underlying molecular mechanisms remain to be elucidated. Here, we show that GABARAP/GABARAPL1 directly binds to a previously unappreciated region in the γ2 subunit of GABAAR. We demonstrate that GABARAP functions to stabilize GABAARs via promoting its trafficking pathway instead of blocking receptor endocytosis. The GABARAPL1–γ2-GABAAR crystal structure reveals the mechanisms underlying the complex formation. We provide evidence showing that phosphorylation of γ2-GABAAR differentially modulate the receptor’s binding to GABARAP and the clathrin adaptor protein AP2. Finally, we demonstrate that GABAergic synaptic currents are reduced upon specific blockage of the GABARAP–GABAAR complex formation. Collectively, our results reveal that GABARAP/GABARAPL1, but not other members of the Atg8 family proteins, specifically regulates synaptic localization of GABAARs via modulating the trafficking of the receptor.

Date: 2021
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DOI: 10.1038/s41467-020-20624-z

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