For instance, many of the mechanisms supporting the polarized targeting of KARs to different neuronal populations are unknown. Recently, two integral membrane proteins have been identified that seem to be true auxiliary subunits of KARs (Zhang et al., 2009, Straub et al., 2011a and Tang et al., 2011). Neuropilin Tolloid-like 1 and Neuropilin Tolloid-like 2 (Neto1 and Neto2) are auxiliary proteins of native Anti-diabetic Compound Library KARs that exert an important influence on their function. Indeed, these proteins radically alter the gating properties of KARs, accounting for a number of previously
unexplained properties of these receptors (see Copits and Swanson, 2012, Lerma, 2011 and Tomita and Castillo, 2012 for recent reviews). Neto1 and Neto2 share an identical and unique domain structure, representing a novel subfamily of transmembrane proteins containing CUB and LDLa domains. Neto1 was first identified as a protein that interacts with the NMDA receptor (Ng et al., selleck screening library 2009), although a number of studies then illustrated that it has a more striking influence on the function of KARs. In general, the coexpression of Neto1 and Neto2 with KARs
in recombinant systems alters the gating properties of the latter. The most obvious effect is that the onset of the desensitization of kainate-evoked responses decelerates (Copits et al., 2011, Straub et al., 2011b and Fisher and Mott, 2013), while recovery from the desensitized state accelerates. This modulation implies that the kainate-induced steady current persists for longer periods in the presence of an agonist (e.g., Fisher and Mott, 2013). This effect is evident for all subunits and reconciles the properties of recombinant receptors with the reported action of kainate not in more physiological preparations, where it behaves as a strong depolarizing agent. Moreover,
the rapid deactivation of kainate-induced currents upon agonist removal is also decelerated in the presence of Neto, suggesting an increase in the steady-state affinity of KARs when associated to Neto. Indeed, equilibrium agonist affinity substantially increased in the presence of Neto, again reconciling the properties of recombinant and native KARs. A prominent feature of KAR-mediated excitatory postsynaptic currents (EPSCKARs) is that they are characteristically slower and smaller than AMPAR-mediated EPSCs (Castillo et al., 1997, Vignes et al., 1998 and Frerking et al., 1998). This cannot be anticipated from the properties of recombinant receptors, since single KARs and AMPARs have similar affinity and activation-inactivation kinetics (see Lerma, 1997). A prominent perisynaptic localization of KARs was also ruled out (Castillo et al., 1997) and if both receptor subtypes colocalize at the synapse, one would expect similar kinetics for the KAR- and AMPAR-mediated synaptic responses. Although the subunit composition of KARs may have an influence in EPSC kinetics (Contractor et al., 2001, Barberis et al., 2008 and Fernandes et al.