Structural basis of GABARAP-mediated GABA<sub>A</sub> receptor trafficking and functions on GABAergic synaptic transmission.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 33436612.
- Also identified by DOI 10.1038/s41467-020-20624-z and PMC identifier 7803741.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
GABA<sub>A</sub> receptors (GABA<sub>A</sub>Rs) are the primary fast inhibitory ion channels in the central nervous system. Dysfunction of trafficking and localization of GABA<sub>A</sub>Rs to cell membranes is clinically associated with severe psychiatric disorders in humans. The GABARAP protein is known to support the stability of GABA<sub>A</sub>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<sub>A</sub>R. We demonstrate that GABARAP functions to stabilize GABA<sub>A</sub>Rs via promoting its trafficking pathway instead of blocking receptor endocytosis. The GABARAPL1-γ2-GABA<sub>A</sub>R crystal structure reveals the mechanisms underlying the complex formation. We provide evidence showing that phosphorylation of γ2-GABA<sub>A</sub>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<sub>A</sub>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<sub>A</sub>Rs via modulating the trafficking of the receptor.
Medical subject headings
- Apoptosis Regulatory Proteins
- GABAergic Neurons
- Microtubule-Associated Proteins
- Receptors, GABA-A
- Synaptic Transmission