GABAA-receptor-associated protein links GABAA receptors and the cytoskeleton

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Abstract
Type-A receptors for the neurotransmitter GABA (γ-aminobutyric acid) are ligand-gated chloride channels that mediate inhibitory neurotransmission. Each subunit of the pentameric receptor protein has ligand-binding sites in the amino-terminal extracellular domain and four membrane-spanning regions, one of which forms a wall of the ion channel1. Each subunit also has a large intracellular loop that may be a target for protein kinases and be required for subcellular targeting and membrane clustering of the receptor, perhaps by anchoring the receptor to the cytoskeleton2,3,4. Neurotransmitter receptors need to be positioned in high density in the cell membrane at sites postsynaptic to nerve terminals releasing that neurotransmitter. Other members of the superfamily of ligand-gated ion-channel receptors associate in postsynaptic-membrane clusters by binding to the proteins rapsyn or gephyrin5,6,7. Here we identify a new cellular protein, GABAA-receptor-associated protein (GABARAP), which can interact with the γ2 subunit of GABAA receptors. GABARAP binds to GABAA receptors both in vitro and in vivo, and co-localizes with the punctate staining of GABAA receptors on cultured cortical neurons. Sequence analysis shows similarity between GABARAP and light chain-3 of microtubule-associated proteins 1A and 1B. Moreover, the N terminus of GABARAP is highly positively charged and features a putative tubulin-binding motif. The interactions among GABAA receptors, GABARAP and tubulin suggest a mechanism for the targeting and clustering of GABAA receptors.