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

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