, 2004) and by an embryonic lethal phenotype of knockin mice in which the γ2 Tyr365/367 residues were mutated to phenylalanine, which interferes with AP2 binding (Tretter et al., 2009). Heterozygous γ2Y365/7F mice, however, are viable. In the stratum pyramidale of the

hippocampus they show a CA3-region-specific increase in the postsynaptic accumulation of GABAARs, suggesting different basal levels of γ2 Tyr365/367 phosphorylation in the CA3 versus CA1 region. The lethal phenotype of homozygous γ2Y365/7F mutants indicates that excessive GABAergic transmission is detrimental during early development, probably due to excessive GABAergic excitation, which may HIF inhibitor interfere with normal neurogenesis and neural migration (Wang and Kriegstein, 2009). Collectively, there is now conclusive evidence that GABAARs are subject to at least two major mechanisms of regulated endocytosis. These mechanisms involve

different phospho-sensitive interactions of the clathrin adaptor AP2 with β and γ2 subunits, respectively. The phospho-states of the relevant β and γ2 subunit motifs are subject to regulation by multiple Ser/Thr and Tyr kinases, as well as phosphatases and their respective adaptor proteins. Dynamic changes in the phosphorylation state of NSF and PRIP and their interaction with the AP2 binding site of β subunits provide additional levels of regulation. Future experiments will need to address whether NSF and PRIP compete with AP2 for GABAAR interaction and whether their interaction with GABAARs is regulated by phosphorylation of GABAARs. The decision of whether

buy Bortezomib endocytosed GABAARs are recycled or degraded is regulated by interaction of GABAAR β1-3 subunits with huntingtin-associated protein 1 (HAP1) (Figure 4) (Kittler et al., 2004b). HAP1 interacts with the Huntington disease protein huntingtin (Li et al., 1995 and Li et al., 2002) and is involved in motor-protein-dependent transport of neuronal cargo (Engelender et al., 1997, Gauthier et al., 2004 and McGuire et al., 2006). When overexpressed in cultured neurons, HAP1 interferes with the degradation of endocytosed GABAARs and thereby increases Non-specific serine/threonine protein kinase the recycling and surface expression of GABAARs (Kittler et al., 2004b). More recent experiments have identified HAP1 as an adaptor for the kinesin superfamily motor protein 5 (KIF5), interacting directly with all three isoforms (A-C) of KIF5 heavy chains (Twelvetrees et al., 2010). HAP1, KIF5 heavy chains and γ2-containing GABAARs are partly colocalized in dendrites and can be isolated as a complex from brain lysates. Moreover, live imaging and electrophysiological recordings revealed that HAP1-KIF5-dependent vesicular trafficking controls the delivery of GABAARs to the plasma membrane and thereby promotes the function of GABAergic inhibitory synapses.