Curiously, the kinetics of KARs imposed by Neto protein is remarkably similar to those of NMDARs (see Figure 1). The difference between NMDAR activation kinetics and that of the faster AMPARs provides adequate timing for activation, since Pfizer Licensed Compound Library in vitro the Mg2+ blockade implies that NMDAR activation would not be operative until sufficient membrane depolarization is attained. In contrast, the functional significance of the slower kinetics of KARs is starting to be illustrated by examples that provide comprehensive roles
for such a prolonged current in synaptic integration (Frerking and Ohliger-Frerking, 2002, Goldin et al., 2007, Sachidhanandam et al., 2009 and Pinheiro et al., 2013; see Figure 1). Another striking action of Neto1 and Neto2 is that association with these proteins greatly reduces inward rectification of KAR-mediated currents without modifying Ca2+ permeability (Fisher and Mott, 2012). It seems that three positive charges (RKK) in the C-terminal of Neto proteins preclude internal polyamine blockade of KAR channel. This effect is reminiscent of stargazin in AMPARs (Soto et al., 2007). However, the functional Alectinib ic50 implication of this action remains to be defined. Apart from the clear effect of Netos on KAR channel gating and on current amplitudes (see Copits and Swanson, 2012), it remains unclear whether Neto proteins are involved
in KAR targeting to the synapse, although there is weak evidence indicating that this may be possible. Cultured hippocampal neurons express native KARs, but these are not targeted to synapses (Lerma et al., 1997). However, a small proportion of ESPCs may be mediated by KARs when such cells are transfected with Neto2 and GluK1, indicating that exogenous Neto2 may target a small proportion of exogenous GluK1 to synapses (Copits et al., 2011). Similar effects were observed in cerebellar granule cells and with GluK2 (Zhang et al., 2009). However, although GluK2 association with PSD95 is reduced in Neto2 null mice 17-DMAG (Alvespimycin) HCl (Tang et al., 2012), the lack of Neto2 expression does
not prevent the presence of endogenous GluK1 or GluK2 in synaptic contacts, despite the fact that synaptic KARs are normally associated with Netos in hippocampal slices. Indeed, KAR-mediated EPSCs in brain slices display distinct kinetics in Neto-deficient animals and EPSCKARs are present in mice even deficient for the two Neto proteins, yet with fast kinetics, consistent with the idea that Netos are not key elements in the targeting of KARs to the synapse (Tang et al., 2011). From these data, it is clear that Netos exert an important influence on KARs, which may vary depending on the subunit combination. However, Neto proteins are not specific to KARs. Indeed, Neto1 was initially identified as a NMDAR interactor.