Association with Intracellular Proteins

The application of the yeast two-hybrid system resulted in the cloning of many intracellular proteins that associate with glutamate receptors, in most cases at their C-terminus. Many of these proteins contain three PDZ domains (named after the proteins PSD-95, Dlg, and ZO1, all of which contain the domain), one src homology domain 3 (SH3), and a guanylate kinase (GK) domain, and thus belong to the PSD-95 or synapse-associated protein (SAP) family (reviewed in ref. 74). Other glutamate receptor-associated proteins do not contain PDZ domains or are signaling molecules. Most of these proteins seem to play a role in receptor membrane insertion [e.g., N-ethylmaleimide-sensitive protein (NSF)], anchoring to the cytoskeleton, clustering, localization, or forming signaling complexes with different signaling molecules.

The interactions of intracellular proteins with AMPA receptors are reviewed by Braithwaite et al. (75). GluR2, GluR3, and GluR4c have a similar C-terminal sequence [IESV(V/I)KI] containing a PDZ-binding domain. This sequence interacts with three proteins containing seven PDZ domains, GRIP and AMPA receptor-binding protein (ABP or GRIP2), and a shorter splice variant of the latter containing six PDZ domains. Moreover, depending the phosphorylation state, they interact with PICK1, which seems to be involved in AMPA receptor clustering and also binds to mGluR7a. Recently, Hayashi et al. (76) proposed that a GluR1 C-terminal sequence (TGL) also interacts with PDZ domains. They showed delivery of GFP-tagged GluR1 into synapses mediated by CAMKII or LTP. The delivery was blocked by mutating the predicted C-terminal PDZ interaction site to AGL, but not by mutating the CAMKII phosphorylation site Ser831. Thus, LTP seemed to depend on GluR1-PDZ domain interactions.

GluR2 interacts with NSF, a protein without PDZ domains and involved in membrane-fusion events, such as exocytosis of synaptic vehicles. NSF seems to act as a chaperone for AMPA receptor (re-)insertion into the membrane (see also review in ref. 77). Moreover, SAP-97 is one the proteins belonging to the SAP family that binds AMPA, kainate, and NMDA receptors, and GluR6 can bind to PSD-95.

NMDA receptor subunits bind to a vast number of SAP proteins, including PSD-95 (NR2A). NR2A, B , and C can also interact with PSD-93/chapsyn 110, SAP97, and SAP102 (e.g., reviewed in ref. 78). These proteins associate to other proteins building a scaffold and bridging to the cytoskele-ton, such as CRIPT - microtubuli, MAP1A, GKAP, SAP90/PSD-95-associated proteins (SAPAPs), or neuroligin (see section 3.8.). Proteins lacking PDZ domains but interacting with NMDA receptor subunits are neurofilament subunit L (NR1), yotiao (NR1), a-actinin (NR1, NR2B), and spectrin (NR2A and B). Additional proteins, with an as-yet unidentified function, were identified recently by mass spectrocsopy (79).

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