Ampar

FIGURE 4 PSD-95 as an anchoring protein for NMDA receptors. See text for explanation.

also binds the ras Guanosine triphosphatase Activating Protein synGAP, whose function is still under investigation but which may regulate the ras/ERK cascade locally at the synapse (see Box 3). PSD-95 also anchors the cytoskeleton through its interations with a protein termed SPAR, which is a Guanosine triphos-phatase Activating Protein (GAP) for rap and also an actin-interacting protein in its own right. Rap helps control the cytoskele-ton indirectly through its target signal transduction processes such as the MAP kinase cascades.

PSD-95 also binds to proteins that seem to be more explicitly structural, such as the scaffolding protein Shank. Shank is another multidomain molecule that links the PSD-95 binding protein Guanylate Kinase-Associated Protein (GKAP) to the actin skeleton through cortactin. Shank also binds to Homer, a metabotropic receptor binding protein. Thus, via Shank and Homer, group I metabotropic receptors coupled to PLC can be localized near the NMDA receptor. Homer also binds the IP3 receptor, which may help localize the ER close to the NMDA receptor, allowing for proximity of intracellular calcium release mechanisms to the principal pathway for extracellular calcium influx, the NMDA receptor.

Genetic deletion of PSD-95 leads to striking alterations in LTP in area CA1— LTP is enhanced (49). This is associated with learning deficits. It is unclear how the loss of PSD-95 leads to the augmentation of LTP—obviously interpretation of the result is difficult because of the many complex roles of PSD-95 at the synapse, as outlined earlier. Overall, the data suggest that PSD-95 is somehow altering the threshold for LTP induction, a result consistent with the idea that PSD-95 and its associated proteins serve as dynamic modulators of NMDA receptor function.

The preceding discussion makes clear that the NMDA receptor does not reside in isolation in the membrane. In fact, Seth Grant's laboratory has clearly established that the NMDA receptor is the anchor for a large multiprotein complex of structural proteins and signal transduction components, as discussed in Box 4. This consideration leads to the inclusion of the NMDA receptor in the list of proteins necessary for proper NMDA receptor function (see Table 3). What is meant by this apparent statement of the obvious is that it is important to remember that the NMDA receptor is functioning as much more than a ligand-and-voltage-gated calcium channel. It also is a critical component of the synaptic infrastructure in a physical sense— serving as a membrane anchor for a wide variety of important postsynaptic proteins.

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