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, Chao Wang
Abstract
Abstract 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.