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

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