bRegulation of the activity of N-methyl-D-aspartate receptors (NMDARs) at glutamatergic synapses is essential for certain forms of synaptic plasticity underlying learning and memory and is also associated with neurotoxicity and neurodegenerative diseases. In this report, we investigate the role of Src-like adaptor protein (Slap) in NMDA receptor signaling. We present data showing that in dissociated neuronal cultures, activation of ephrin (Eph) receptors by chimeric preclustered 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 prolonged activation of EphB receptors. Using established heterologous systems, we examined whether Slap is an integral part of NMDA receptor signaling. Our results showed that Slap does not alter baseline activity of NMDA receptors and does not affect 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 occurring in an activity-dependent manner, suggesting that Slap is part of a mechanism that homeostatically modulates the levels of NMDA receptors. In an effort to identify genes involved in cortical development, we have previously cloned slap, which encodes a Src-like adaptor protein (Slap) (1). slap is expressed strongly in the forebrain, but its function there remains unknown. slap encodes a 34-kDa protein containing SH2 and SH3 domains followed by a unique 104-amino-acid COOH terminal. Similar to results seen with members of the Src family kinases (SFKs), myristoylation at the NH2 terminus targets Slap to cellular membranes (2). Slap has been studied in the immune system, where it inhibits T-cell receptor (TCR) signaling (3) and is involved in the internalization and degradation of the TCR subunit (4). Furthermore, Slap abrogates the mitogenic response to platelet-derived growth factors (PDGFs) in NIH 3T3 fibroblasts, antagonizing the mitotic activity of Src kinase (5).Slap was initially identified in a yeast two-hybrid screen using the cytoplasmic tail of EphrinA2 as bait (6). Ephrin (Eph) receptors constitute the largest known family of receptor tyrosine kinases and, together with their membrane-bound ligands (eph ligands), have been implicated in a variety of patterning events during the development of the central nervous system (7-21). Ephs and their ligands act as contact-dependent adhesive molecules and are implicated in the development and function of synapses. They are divided into two classes (EphA and EphB), based on sequence homologies and binding specificity (22). EphBs have established roles in the formation of synapses, transforming dendritic filopodia to spines and clustering and phosphorylating Nmethyl-D-aspartate receptors (NMDARs) (7,9,23), and are implicated in...
Alix/AIP1 is an adaptor protein involved in apoptosis, endocytic membrane trafficking and brain development. Alix has been found within the human postsynaptic density (PSD) and, since NMDA receptors (NMDARs) are central components of the PSD, we hypothesized that the close proximity of both proteins may allow Alix to influence the downstream pathways following NMDAR activation. NMDARs play important roles in excitotoxicity and we evaluated the effects of recombinant Alix in an NMDAR cell death assay. Overexpression of Alix with NMDARs increases the potency of NMDAR‐ induced cell death compared to cells expressing only NMDARs, and this requires expression of the Alix C‐terminal region. Therefore, we demonstrate a previously unreported role for Alix as a potential modulator of NMDAR function.
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