Third, they play an influential role in the maturation of neural circuits during development. These roles are frequently fulfilled in an unconventional way given that KARs can signal by activating a G protein, behaving more like a metabotropic receptor than an ion channel. This noncanonical signaling is totally unexpected considering that the three iGluRs share a common molecular design, as recently revealed by their crystal structure (Mayer, 2005, Furukawa et al.,

2005 and Gouaux, 2004). It is difficult to do justice to the literature generated on KARs over the years in the short space available, and indeed, there are several reviews find more that have described many of the molecular, biophysical, pharmacological, and functional www.selleckchem.com/products/Romidepsin-FK228.html aspects of these receptors (Rodrigues and Lerma, 2012, Contractor et al., 2011, Lerma et al., 2001, Lerma, 2003, Lerma, 2006, Copits and Swanson, 2012, Vincent and Mulle, 2009, Coussen and Mulle, 2006, Pinheiro and Mulle, 2006, Tomita and Castillo, 2012, Jaskolski et al., 2005 and Matute, 2011). Hence, in this Review we will focus primarily on the data that have influenced our notion of KAR function and the wealth of new data available implicating KARs in brain pathology. To date,

and like many other receptors and channels, a whole set of proteins have been identified that can interact with KAR subunits (Table 1). Indeed, the identification of these proteins has changed our view on how KARs function and provided insight into the discrepancies between native and recombinant KAR properties. While the exact role of these interactions still remains to be unambiguously established, the role of KARs in physiology will be difficult to understand without taking into account the contribution of these proteins. For instance, KARs and many of these proteins seem to undergo transient interactions that promote receptor trafficking, regulating their surface expression. PDZ motif-containing proteins such as postsynaptic density protein 95 (PSD-95), protein interacting with C kinase-1 (PICK1), and glutamate receptor interacting

protein (GRIP) seem to be relevant for the stabilization of KARs at the synaptic membrane (Hirbec Urease et al., 2003). However, PDZ-binding motifs in the C terminus of KAR subunits are also present in other glutamate receptors. Thus, these interacting proteins are not selective for KARs. Although interactions with PDZ domains cannot entirely account for the subcellular distribution of KARs, the interaction with PDZ proteins produce apparently different outcomes for these receptors, as these proteins prevent AMPAR internalization but facilitate KAR internalization (Hirbec et al., 2003). It was recently demonstrated that the SNARE protein SNAP-25 is a KAR-interacting protein (Selak et al., 2009).