Regulation Of Ras By Gaps And Gefs

Ras is a low-molecular-weight GTP-binding protein (G protein) classically studied as a target for particular receptor tyrosine kinases. Ras acts as a critical relay in signal transduction by cycling between an active conformational state when bound to GTP, and an inactive state when bound to GDP (see figure). The GTPase, or turn-off activity of ras is dependent on the opposing effects of two distinct classes of regulatory ras-binding molecules; GAPs and GEFs (guanine nucleotide exchange factors). GAPs promote formation of the GDP-ras complex through increasing ras GTPase activity, and thus inactivate ras. GEFs act by catalyzing the exchange of GTP for GDP, causing ras activation. The best-known GEFs fall into two major classes; the son of sevenless (SOS) class and the ras-guanine-nucleotide releasing factor (ras-GRF) class.

It also is important to note that there are three different isoforms of ras: H, N, and K. These different ras types likely have similar functions but they exhibit distinct tissue distributions—all are found in the brain.

Protein Signalling Gap Gefs

Guanine Nucleotide Exchange Factor Proteins (e.g., SOS, cAMPGEF, Ca!*/DAG GEF. ras GRF) BOX 3 Activation of ras. Reproduced from Weeber and Sweatt (94).

the context of retrograde signaling in synaptic plasticity, is that integrins can transduce a signal from inside the cell back out to the extracellular domain. Specifically, phosphorylation of integrins on their cyto-plasmic domain can cause a conformational change in their extracellular domain. Because a postsynaptic integrin molecule can directly bind to another presynaptic integrin molecule, this is a potential mechanism for sending a signal from the postsynaptic compartment back to the presynaptic compartment (i.e., retrograde signaling). Although this idea is still speculative at present, this type of direct conformational signal transduction from post- to presynaptic cells is an appealing idea for allowing coordinated, simultaneous functional changes in both compartments. Although this is not hypothesized to regulate NMDA receptor function specifically, I would be remiss if I did not mention this potentially quite important role for integrins as one potential component of LTP induction.

An additional transmembrane, extracellular-matrix-binding protein that has been directly implicated in LTP induction is Syndecan-3. Inhibition of this molecule using various approaches leads to deficits in LTP (42). Syndecan-3 binds heparan sulfates in the extracellular space, which are components of the glycosamino-glycan family of molecules present there. Syndecan-3 associates with the tyrosine kinase fyn, which might regulate NMDA receptor activity through direct tyrosine phosphorylation. The cell adhesion molecules L1 and Neural Cell Adhesion Molecule (N-CAM) have also been implicated in the expression of LTP in some studies, however, recent results from knockout mice have suggested that loss of these molecules does not lead to LTP deficits (43-45). Finally, the N-cadherin subtype of cell adhesion molecule has been implicated in LTP induction and maintenance (see reference 46 for a review). A likely role for the cadherins is in stabilizing strong connections between the presynaptic and postsynaptic membranes, although like other cell adhesion molecules the cadherins also interact with and can regulate the actin cytoskeleton.

B. Presynaptic Processes

It is a statement of the obvious that any presynaptic process that regulates glutamate release can impinge upon the likelihood of LTP induction by controlling the level of synaptic glutamate that is attained. We discussed a number of specific examples of this type of mechanism in the last chapter—for example, BDNF receptor regulation of LTP induction and the potential role for alterations in glutamate re-uptake as a mechanism for controlling NMDA receptor desensitization. I will not reiterate the details here, but simply note that they fit equally well into a discussion of regu lating NMDA receptor function as they did in the prior context of "complexities of LTP."

Of course, many other specific molecular processes are involved in mediating and modulating the likelihood of vesicle fusion presynaptically, and thus modulating the likelihood of NMDA receptor activation postsynaptically. A complete treatment of this area of plasticity would require an entire monograph in its own right; moreover, many of the molecular details of these processing are still being worked out. For the present purposes, I will limit myself to pointing out that knockouts and inhibitors that affect the presynaptic infrastructure are quite likely to disrupt indirectly the proper function of the NMDA receptor as well.

C. Anchoring and Interacting Proteins of the Postsynaptic Compartment

Postsynaptic Density Proteins

The postsynaptic density warrants discussion as a cellular organelle in its own right. It is a multiprotein assembly that is the organizing center for many receptors and effectors, and the cytoskeleton, in the postsynaptic compartment (47, 48).

PSD-95 is a protein enriched in the postsynaptic density and a prominent player in this context (49). Identification of this protein by Mary Kennedy helped launch a great increase in our understanding of the molecular basis for the organization of the complex postsynaptic infrastructure. What follows is a brief overview summarizing many years of work by many laboratories, including those of Mary Kennedy, Morgan Sheng, and Rick Huganir.

PSD-95 binds to NMDA receptors (specifically the NR2 subunit) postsynap-tically and serves as a multidomain anchoring protein for a large number of scaffolding and structural proteins postsynaptically (see Figure 4). PSD-95 helps anchor nitric oxide synthase (NOS), localizing this source of the reactive nitrogen species NO. PSD-95

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

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