Wang H, Bedford F K, Brandon N J, Moss S J, Olsen R W
Molecular Biology Institute, University of California, Los Angeles 90095, USA.
Nature. 1999 Jan 7;397(6714):69-72. doi: 10.1038/16264.
Type-A receptors for the neurotransmitter GABA (gamma-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 channel. 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 cytoskeleton. 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 gephyrin. Here we identify a new cellular protein, GABA(A)-receptor-associated protein (GABARAP), which can interact with the gamma2 subunit of GABA(A) receptors. GABARAP binds to GABA(A) receptors both in vitro and in vivo, and co-localizes with the punctate staining of GABA(A) 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 GABA(A) receptors, GABARAP and tubulin suggest a mechanism for the targeting and clustering of GABA(A) receptors.
神经递质γ-氨基丁酸（GABA）的A型受体是配体门控氯离子通道，介导抑制性神经传递。五聚体受体蛋白的每个亚基在氨基末端细胞外结构域有配体结合位点和四个跨膜区域，其中一个跨膜区域形成离子通道的壁。每个亚基还有一个大的细胞内环，可能是蛋白激酶的作用靶点，并且可能通过将受体锚定到细胞骨架上，对于受体的亚细胞定位和膜聚集是必需的。神经递质受体需要高密度地定位在释放该神经递质的神经末梢突触后的细胞膜位点上。配体门控离子通道受体超家族的其他成员通过与rapsyn或gephyrin蛋白结合，在突触后膜簇中聚集。在这里，我们鉴定出一种新的细胞蛋白，GABA（A）受体相关蛋白（GABARAP），它可以与GABA（A）受体的γ2亚基相互作用。GABARAP在体外和体内均与GABA（A）受体结合，并与培养的皮质神经元上GABA（A）受体的点状染色共定位。序列分析表明GABARAP与微管相关蛋白1A和1B的轻链3具有相似性。此外，GABARAP的N末端带高度正电荷，并具有一个假定的微管蛋白结合基序。GABA（A）受体、GABARAP和微管蛋白之间的相互作用提示了一种GABA（A）受体靶向和聚集的机制。
