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

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.

KEYWORDS: {{ getKeywords(articleDetailText.words) }}