Proteins that interact with NMDA receptors

PSD95 | SAP102 | Yotiao | AP2

PSD-95 (Post Synaptic Density protein 95)

Domain structure of PSD95PSD95 interacts with both NR2A and NR2B via PDZ domains 1 and 2 (NR2B prefferentially binds to PDZ2 whereas NR2A binds to both PDZ1 & 2 with equal strength; Kornau et al 1995, Neithammer et al 1996, Hoe et al 2006). In addition, it has recently been reported that the NR2C subunit also interacts directly with PSD-95 (Chen et al 2006), although the exact PDZ domain involved is not known. Little is known about the regulation of the interaction between NMDA receptor and PSD-95, but the association of the NR2B subunit may be blocked by CK2-mediated phosphorylation of the PDZ domain binding site (Chung et al 2004)..... or not (Soto et al 2004).

The function of the PSD-95/NMDAR interaction is to stabilise the receptor at the synaptic membrane (Roche et al 2001, Li et al 2003). However, it also acts as a scaffold protein to bring together other proteins that interact with the NMDA receptors, e.g. synGAP (Kim et al 1998, Chen et al 2002), various kinases e.g PKC (Lin et al 2006) and tyrosine kinases (Liao et al 2000, Kalia & Salter 2003). It also promotes NMDA receptor clustering (e.g. Kim et al 1996) and has been shown to directly modulate channel properties (mean open time; Lin et al 2004).

SAP102 (Synapse-Associated Protein 102)

Domain structure of SAP102SAP102 is another of the MAGUK family of scaffolding proteins related to PSD95. All three PDZ binding domains have been shown to bind the NR2B subunit (Muller et al 1996, Lau et al 1996). It is also interesting to note that the high level of NR2B expression seen early in development matches the high level of SAP102 seen at the same developmental time, prior to the increase in PDS-95 expression (Sans et al 2000).

Given the structural similarities in the PDZ domains of PSD-95 and SAP102, proteins tend to interact with both of these scaffolding proteins (Wenthold et al 2004). Indeed, the knock-out of PSD-95 has little impact on overall synaptic transmission or NMDA receptor expression/localisation suggesting significant functional compensation (Migaud et al 1998).

However, the lack of a palmitoylation site on SAP102 ensures that it does not associate with membranes and so they play different functional roles within the cytoskeleton.

Yotiao

Yotiao is an A-Kinase Achoring Protein (AKAP) that associates with the NR1 subunit (Lin et al 1998). It is a coiled-coil protein that is a splice variant of larger AKAP proteins, AKAP350 (Schmidt et al 1999) and also AKAP450 (Witczak et al 1999). It provides an anchoring point for Protein Kinase A (PKA, Lin et al 1998, Westphal et al 1999, Feliciello et al 1990) as well as Protein Phosphatase 1 (PP1, Westphal et al 1999).

AP-2 (Adaptor Protein-2)

In addition to binding to AMPA receptors, AP-2 is also known to bind to the NR2Aand NR2B subunits of the NMDA receptor. The C-termini of both the subunits interact with the µ2 subunit of AP-2 (Roche et al 2001, Lavezzari et al 2003, Slepnev et al 2000) although only the NR2B C-terminus can induce clathrin-mediated endocytosis (Vissel et al 2001, Lavezzari et al 2004). However, such an internalisation mechanism for the NR2A subunit can be induced following priming of the receptor complex with its co-agonist glycine (Nong et al 2003). In addition, disruption of the AP-2 binding domain or blockade of the binding of AP-2 with inhibitor peptides has been shown to increase the number of synaptic NR2B receptors and to disrupt PDZ domain-mediated control over synaptic localisation (Prybylowski et al 2005)