, 2005). These data would in principle indicate that the subunit interacting with G proteins might be GluK5, either directly or indirectly. There are additional issues that appear at odds with this idea. The involvement of Gq protein does not fit with the PTx sensitivity of the metabotropic actions of KARs described to date (see Rodrigues and Lerma, 2012 and references therein) but, rather, the PTx sensitivity suggests that Gi or Go proteins are likely to be involved in the metabotropic actions of KARs. However, the concomitant involvement of PLC and PKC in most of the metabotropic effects described to date rules out the participation of Gi, leaving the Go protein

as the only strong candidate click here to mediate these effects (e.g., Rozas et al., 2003). Nevertheless, some effects induced by KA are contingent on the inhibition of adenylate cyclase and the subsequent reduction in cAMP would involve Gi protein activation, as also described (Gelsomino et al., 2013 and Negrete-Díaz et al., 2006). Available data clearly

SB203580 molecular weight show that subunit composition alone cannot define the signaling mode triggered by KARs, pointing to interacting partners as candidates likely to determine the mode of action of KARs. However, the existence of proteins that functionally couple KARs and G proteins remains to be demonstrated. It should be also taken into account that some at odds data has been published pointing out that at least part of the noncanonical signaling triggered by KARs may be indirect (Lourenço et al., 2011). Regardless of the specific mechanisms, it is now clear that KARs can no longer be considered simply as ligand-gated ion channels. The increasing number of activities known to be mediated by KARs through this noncanonical signaling, as described below, indicates that this dual signaling is one of the main factors underlying the diverse actions of KARs reported over the years. Unlike AMPAR-mediated these currents, the activation of postsynaptic KARs by synaptically released glutamate yields small

amplitude EPSCs, with slow activation and deactivation kinetics (see Figure 1; Castillo et al., 1997). Moreover, while AMPARs and NMDARs are localized to the postsynaptic density of the vast majority of glutamatergic synapses in the brain, EPSCs mediated by KARs have only been found in a few central synapses, such as in MF to CA3 pyramidal neurons (Castillo et al., 1997 and Vignes and Collingridge, 1997), the contacts between Schaffer collaterals and CA1 hippocampal interneurons (Cossart et al., 1998 and Frerking et al., 1998), between parallel fibers and Golgi cells in the cerebellum (Bureau et al., 2000), at thalamocortical connections (Kidd and Isaac, 1999), in the basolateral amygdala (Li and Rogawski, 1998), in the synapses between afferent sensory fibers and dorsal horn neurons in the spinal cord (Li et al., 1999), and those of parallel fibers and cerebellar Golgi cells (Bureau et al., 2000).