Ye, J., Zou, G., Zhu, R., Kong, C., Miao, C., Zhang, M., ... & Wang, C. (2021). Nature Communications, 12(1), 297.

GABA_A receptors (GABA_ARs) are the primary fast inhibitory ion channels in the central nervous system. Dysfunction of trafficking and localization of GABA_ARs to cell membranes is clinically associated with severe psychiatric disorders in humans. The GABARAP protein is known to support the stability of GABA_ARs 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 GABA_AR. We demonstrate that GABARAP functions to stabilize GABA_ARs via promoting its trafficking pathway instead of blocking receptor endocytosis. The GABARAPL1–γ2-GABA_AR crystal structure reveals the mechanisms underlying the complex formation. We provide evidence showing that phosphorylation of γ2-GABA_AR 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–GABA_AR complex formation. Collectively, our results reveal that GABARAP/GABARAPL1, but not other members of the Atg8 family proteins, specifically regulates synaptic localization of GABA_ARs via modulating the trafficking of the receptor.

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