, 2013). These data raise the possibility that Neto proteins play a more wide-ranging role than initially anticipated. Nevertheless, the interesting question that remains to be answered is whether the association of Neto1/2 with KARs could be regulated by physiological signals, and under what circumstances this occurs. Since KARs are fully operational in the absence of Neto, it is possible that two populations of KARs might exist, those with and without Neto probably fulfilling complementary functional roles. Recently,

the group of Maricq has identified in the worm C. elegans SOL-2, a CUB-domain protein that associates with both the related auxiliary subunit SOL-1 and with the GLR-1 AMPAR ( Wang et al., 2012). Like Neto1, Osimertinib manufacturer SOL-2 contributes to the kinetics of receptor desensitization and is an essential component of AMPAR complexes at worm synapses. These data indicate that several different interacting proteins could form the receptor complex at synapses. One unique feature of KARs is that their channel gating requires external monovalent cations and anions. This ion-dependent channel gating differentiates KARs from other ligand-gated channels, including

the closely related NMDARs and AMPARs (Paternain et al., 2003 and Bowie, 2002; see Bowie, 2010 for a review). Indeed, crystallographic studies have revealed the existence of an ion binding pocket in KAR subunits (Plested and Mayer, 2007 and Plested et al., 2008). The absolute requirement of ion binding for channel opening learn more indicates that KAR activity would be abolished if this binding site remained unoccupied, prompting the suggestion that this site might be used as a target for specific allosteric modulation

of KARs by external agents. The question as to what might be the physiological role of such a strict dependence of the channel gate has not been answered yet but prompted some possibilities. PD184352 (CI-1040) For instance, under intense neuronal activity, a situation under which external Na+ levels drop, activation of KARs would be limited, constituting a brake for tissue damage. Indeed, a large fraction of KARs seems to have unoccupied the cation binding site at physiological salt concentrations, making them insensitive to activation by released glutamate (Plested et al., 2008). Much work remains to be done to figure out whether this fraction of incompetent KARs could be modulated up and down as a way to regulate the weight of these receptors in, for instance, synaptic transmission. High-resolution structural analysis has revealed many similarities between the three glutamate receptor families. However, unlike AMPA and NMDA receptors, KARs appear to also signal through an unconventional metabotropic mechanism involving G proteins and second messengers at inhibitory CA1 hippocampal synapses (Rodríguez-Moreno et al.