, 2008). In this way

the number of GABAARs at the synapse can be modulated without altering the number of receptors at the cell surface (Jacob et al., 2005; Thomas et al., 2005), providing a mechanism for rapid changes in the efficacy of synaptic transmission. Clearly, GABAARs are ‘trapped’ and stabilised by synapses, probably by interactions with proteins in the postsynaptic density and/or synaptic cleft. The refinement of this process at individual synapses to ensure the clustering of specific receptor subtypes appears not to involve the intracellular binding partners so far identified, as most exhibit little or no α-subunit specificity. Another important aspect of GABAAR regulation at the neuronal cell surface relates Stem Cells inhibitor to the overall levels of expression of these receptors and thus their availability for recruitment to specific synapses. The number of GABAARs at the cell surface is determined by their rate of insertion into the plasma membrane following their synthesis and assembly within the ER, their maturation within the Golgi

apparatus, and their rate of removal from the plasma membrane by endocytosis (Arancibia-Carcamo & Kittler, 2009). What remains unclear is whether newly synthesized receptors are inserted directly into the postsynaptic membrane, or only following lateral diffusion from extrasynaptic sites. A number of proteins associated with GABAARs have been implicated in the maturation of GABAARs following their synthesis through the secretory pathways. Within the ER, newly synthesised GABAARs GDC-0980 nmr associate with the chaperone proteins BiP (immunoglobulin binding protein) and calnexin (Connolly et al., 1996b), which

may provide important quality control, or with PLIC-1 (a ubiquitin-like protein; Bedford et al., 2001). PLIC-1 was demonstrated to interact directly with all GABAARs and subunits, stabilizing receptor assemblies and protecting Y-27632 2HCl them from proteosome-dependent degradation. In addition, the interaction with PLIC-1 promotes the insertion of GABAARs into the plasma membrane (Saliba et al., 2008). Another GABAAR-associated protein that is implicated in the maturation of newly synthesised receptors within the Golgi apparatus is BIG2 (brefeldin A-inhibited GDP/GTP exchange factor 2), which directly associates with β-subunits and co-localizes with GABAARs within the trans-Golgi network (Charych et al., 2004). Again, despite the identification of a growing number of proteins that influence the insertion of GABAARs into the plasma membrane, no well-characterised mechanisms that differentiate between synaptic and extrasynaptic insertion and none that can be predicted to distinguish between GABAAR subtypes have yet been identified.