Activation of EphA Receptors Mediates the Recruitment of the Adaptor Protein Slap, Contributing to the Downregulation of N-Methyl-D-Aspartate Receptors

Regulation of the activity of NMDA receptors at glutamatergic synapses is essential for certain forms of synaptic plasticity underlying learning and memory and is also associated to neurotoxicity and neurodegenerative diseases. In this report we investigate the role of the Src Like Adaptor Protein (Slap) in NMDA receptor signalling. We present data showing that in dissociated neuronal cultures, activation of Ephrin receptors by chimeric pre-clustered eph-Fc ligands leads to recruitment of Slap and NMDA receptors at the sites of Eph receptor activation. Interestingly, our data suggest that prolonged activation of EphA receptors is as efficient in recruiting Slap and NMDA receptors as EphBs. Using established heterologous systems we examined whether Slap is an integral part of NMDA receptor signalling. Our results showed that Slap does not alter baseline activity of NMDA receptors, nor does it affect a Src dependent potentiation of NMDA receptor currents in Xenopus oocytes. We also demonstrate that Slap reduces excitotoxic cell death triggered by activation of NMDARs in HEK293 cells. Finally, we present evidence showing reduced levels of NMDA receptors in the presence of Slap in an activity-dependent manner, suggesting that Slap is part of a mechanism that homeostatically modulates the levels of NMDA receptors.