NMDA receptors domain

Grb-2 facilitates the transduction of an extracellular stimulus to an intracellular signaling pathway, (b) The adaptor protein PSD-95 associates through one of its three PDZ domains with the N-methyl-D-aspartic acid (NMDA) receptor. Another PDZ domain associates with a PDZ domain from neuronal nitric oxide synthase (nNOS). Through its interaction with PSD-95, nNOS is localized to the NMDA receptor. Stimulation by glutamate induces an influx of calcium, which activates nNOS, resulting in the production of nitric oxide. 

In addition to the regulatory mechanisms discussed above, an interesting form of Ca2+-dependent inactivation of NMDA receptors is brought about by calmodulin. Activated by Ca2+ entry, calmodulin interacts with the C-terminal domain of the NR1 subunit (Fig 15-4B) this interaction causes inactivation of the receptor manifested... 

The NR2 subunit of the NMDA receptor binds to PDZ domains of PSD95 with its cytoplasmic C-terminus. PSD95 also binds a-actinin, which again binds to filamentous actin (F-actin), a main cytoskeletal protein in dendritic spines. In this manner PSD95 anchors the NMDA receptor to the cytoskeleton of the dendritic spine. 

Fayyazuddin, A., Villarroel, A., Le Goff, A., Lerma, J., and Neyton, J. (2000) Four residues of the extracellular N-terminal domain of the NR2A subunit control high-affinity Zn2+ binding to NMDA receptors. Neuron 25,683-694. 

Kornau HC, Schenker LT, Kennedy MB, Seeburg PH. 1995. Domain interaction between NMDA receptor subunits and... 

Fig. 5 Schematic of the NMDA receptor channel binding domain for...

The protein PSD-95 is an example of a PDZ-containing protein (review Craven and Bredt, 1998). PSD-95 is found in postsynaptic cells where, via its PDZ domains, it mediates interactions with intracellular domains of receptors such as the NMDA receptor (see 16.4.2.1). The InaD protein which is composed solely of PDZ domains has an adaptor function in the vision process in Drosophila (see 8.2.5). 

Fig. 16.11. Model of the association of Fyn kinase with the NMDA receptor The NMDA receptor is shown as a tetramer of NRl and NR2 subunits. The C-terminal tail of NR2 interacts with PDZ2 of PSD-95. The protein tyrosine kinase Fyn is assumed to bind to PDZ3 of PSD-95 via its SH2 domain. Fyn also is anchored to the ceU membrane via its myristoylated N-terminus. GK guanylate kinase domain of PSD-95. According to Sala and Sheng (1999), with permission.

It is assumed that the PSD-95 protein functions as an organizer of large protein complexes in the postsynaptic membrane, since other signal proteins such as a NO synthase and a Ras-GAP protein can also specifically bind to the PDZ domain or other domains of PSD-95. In this way, the NMDA receptor is coupled via PSD-95 to other signal proteins in the cell, whereby the NMDA receptor is directly linked to other signal conduction. 

The discovery of potent and selective agonists and antagonists (Figs. 2.1, 2.2, and 2.3) has resulted in extensive information on the NMDA receptor-channel complex (Wood et al., 1990 Fagg and Baud, 1988). It consists of four domains (1) the transmitter recognition site with which NMDA and L-glutamate interact ... 

Petrou S., Ordway R. W., Singer J. J., and Walsh J. V. (1993). A putative fatty acid-binding domain of the NMDA receptor. Trends Biochem. Sci. 18 41 12. 

NMDA receptors are clustered at postsynaptic sites where cytoplasmic adapter proteins anchor them to the cytoskeleton. Some adapter proteins contain a PDZ domain while others lack this. The PDZ domain is a protein-protein interaction motif of approximately 90 amino acids, which in most cases, binds their target proteins at the C-terminus ends. For example a PDZ domain protein, PSD-95, interacts with the C-terminus of the NR2 subunit. Its interaction with tubulin-based cytoskele-tal protein is mediated by a novel postsynaptic protein called CRIPT (Niethammer et al., 1998). Thus NR1 and NR2 subunits and their related proteins are crucial for efficient gating of NMDA receptor channels. 

Schrattenholz A. and Soskic V. (2006). NMDA receptors are not alone dynamic regulation of NMDA receptor structure and function by neuregulins and transient cholesterol-rich membrane domains leads to disease-specific nuances of glutamate signalling. Curr. Top. Medicinal Chem. 6 663-686. 

PDZ domain suppression of an ER retention signal in NMDA receptor NR1 splice variants. Neuron 28 887-898. 

Tingley WG, Roche KW, Thompson AK, Huganir RL. 1993. Regulation of NMDA receptor phosphorylation by alternative splicing of the C-terminal domain. Nature 364 70-73. 

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