In GluK3, this glycine residue is replaced by D759, producing unique rapid desensitization, whereas in GluK4 and GluK5, the asparagine substitution at this position

would likely not destabilize the LBD dimer interface, imparting different gating properties to these receptors. CT99021 clinical trial Zinc can modulate excitatory synaptic transmission through multiple mechanisms, which are not all well described (Paoletti et al., 2009). Although the inhibitory regulation of postsynaptic glutamate receptors, principally NMDARs, appears as a primary function of synaptic zinc, other potential roles in the regulation of synaptic transmission have also been proposed by Paoletti et al. (2009). Technical limitations have yet precluded a direct measurement of zinc in the synaptic cleft. However, the peak concentration was initially estimated to be in the order of 100 μM (Vogt et al., 2000). This value

Epigenetic inhibitor cost is well within the range of efficacy for the allosteric potentiation of GluK3 by zinc but may be overestimated and may depend on experimental conditions (Paoletti et al., 2009). Moreover, simultaneous application of zinc and glutamate does not potentiate GluK3-mediated currents (data not shown), which likely excludes an effect of zinc during low-frequency stimulation. However, high-frequency trains of synaptic stimulation are thought to trigger a substantial increase in extracellular zinc, and the accumulated zinc could potentiate presynaptic GluK2/GluK3 receptors present at hippocampal mossy fiber synapses (Pinheiro et al., 2007). Interestingly, it has been

shown that vesicular zinc is required for presynaptic LTP at hippocampal mossy fiber synapses by a yet undisclosed mechanism (Pan et al., 2011). This result can be correlated with the fact that mossy fiber LTP is absent in GluK3−/− mice (Pinheiro et al., 2007). The positive allosteric modulation of these presynaptic GluK2/GluK3 receptors may impart increased sensitivity to glutamate and prolonged channel opening, inducing a possible increase Bay 11-7085 in presynaptic Ca2+ influx. Hence, allosteric modulation of presynaptic GluK3 receptors may be one of the mechanisms by which zinc promotes presynaptic long-term potentiation. In conclusion, we have identified zinc as a positive allosteric modulator of presynaptic KARs, with a potential role in synaptic plasticity. Our structure-function analyses lend further support to the notion that the stability of the LBD dimer interface is essential for dictating the desensitization properties of KARs. Our data help explain the fast desensitization properties of GluK3 as compared to GluK2 and pinpoint a single amino acid residue in the upper lobe of the clamshell of the GluK3 LBD, D759, as responsible for the specific properties of GluK3.