Interestingly, these results implied that SNAP25, classically regarded as a member of the exocytotic machinery, may be also involved in endocytosis (Selak et al., 2009). This view has been recently supported by a report defining a role for SNAP25 in clathrin-dependent endocytosis at conventional synapses (Zhang et al., 2013). KARs at these synapses may also contain GluK2 subunits and, recently, it was proposed that this mechanism of LTD requires the synergistic SUMOylation of GluK2 subunits, initiated by PKC phosphorylation (Chamberlain et al., 2012). This new mechanism expands the repertoire of events associated with synaptic plasticity. The possibility of modifying information

this website transfer at this level has been further illustrated by the recent observation that CaMKII-mediated phosphorylation of GluK5 subunits also depresses a KAR-mediated synaptic component at CA3 synapses (Carta et al., 2013). A spike timing-dependent plasticity protocol, known to activate CaMKII in a number

of synapses and induce AMPAR LTP, induces phosphorylation of GluK5-containing receptors in MF-CA3 synapses, resulting in LTD of the KAR-mediated synaptic component. Rather than involving endocytosis of KARs, this depression is evoked by the lateral diffusion of these receptors upon uncoupling of the PSD-95 scaffolding protein at the postsynaptic density (Carta et al., 2013; see also Copits and Swanson, 2013a). Additional proteins that interact and directly modulate the properties of KARs have also been identified. These include proteins such as kainate Venetoclax ic50 receptor interacting

protein for GluR6 (KRIP6; Laezza et al., 2007), a protein that belongs to the BTB/kelch family and that binds to a C-terminal motif distinct to the PDZ binding motif. Coexpression of KRIP6 with GluK2 reduces both the peak current and steady-state desensitization in recombinant systems, as well as that of native KARs. Interestingly, KRIP6 does not affect the surface expression of GluK2 receptors, NET1 indicating that the interaction with this protein only affects channel gating. Another BTB/kelch family member, actinfilin, is also thought to interact with GluK2 subunits (Salinas et al., 2006), this protein promoting the degradation of GluK2 receptors by acting as a scaffold to link this subunit to the E3 ubiquitin-ligase complex. In this way, actinfilin regulates the synaptic expression of receptors containing GluK2 (Salinas et al., 2006), although more work will be necessary to reveal what is the physiological impact of these BTB/kelch proteins. For instance, it is known that KRIP6 can interact with PICK1, forming clusters that lack GluK2 and preventing the mutual regulation of GluK2 containing KARs (Laezza et al., 2008). A number of studies have identified trafficking and targeting motifs in KAR subunits and increased our knowledge of the mechanisms controlling KAR targeting and surface expression (see reviews by Pinheiro and Mulle, 2006 and Contractor et al., 2011).