Postsynaptic density PSD

Among the GluRs, NMDA receptors are biochemically the most tightly associated with the postsynaptic density (PSD), a morphological characteristic of excitatory synapses that is specialized for postsynaptic signal transduction (Kennedy, 1997 Ziff, 1997). Presumably, NMDA receptors are anchored in the PSD through specific protein-protein interactions mediated by the cytoplasmic domains of its constituent subunits. Via these biochemical interactions, NMDA receptors can be linked to the subsynaptic cytoskeleton and coupled to... 

An important function of the PDZ domains lies in the formation of macromolecular associates at the cell membrane (review Pawson and Scott, 1997). PDZ proteins can also provide a framework for clustering of ion channels within specific structures at postsynaptic membranes, known as postsynaptic density, PSD. Major organizers of the PSD appear to be PDZ-containing proteins, e. g., PSD-95, with distinct specificity for binding of downstream signaling proteins. 

Fig. 48. Electron micrograph of the synaptic distribution of immunoreactivity for the GluRl subunit of the AMPA receptor in rat cerebellum as detected by an antibody against the carboxy-terminal (intracellular) region of GluRl. A. A spine (s) emerging from a Purkinje cell dendrite (Pd) establishes an immunopositive type 1 synapse (solid arrows) with a parallel fiber terminal (pft). Intra-cellular immunoreactivity is present inside Bergmann glial cell processes along dendritic elements (e.g., open arrow). B. The peroxidase reaction end-product labels the postsynaptic density (psd) at the intracellular face of the postsynaptic membrane (pom) and not the synaptic cleft between the presyaptic (pem) and postsynaptic (pom) membranes. Scale bars in A = 0.5 /xm, in B = 0.1 jum. Baude et al. (1994).

It is noteworthy that Src-induced increase in NR1-NR2A receptor activity is promoted by the coexpression of postsynaptic density protein known as PSD-95 [37]. PSD-95 is a scaffolding protein consisting of multiple protein-protein interaction domains - three N-terminal PDZ domains, an SH3 domain and a C-terminal guanyl-ate kinase domain. The first two PDZ domains interact with the NR2 C-terminal tails while the third PDZ domain... 

NMDA receptors are anchored in the postsynaptic density (PSD95, 95 kDa), a complex with which over 80 proteins have been associated (see Ch. 15). Postmortem studies have examined the expression of the subunits of the NMDA receptors as well as components of the PSD [29]. In one study in the thalamus, the NR1 and NR2B subunits were decreased in schizophrenia and PSD95, SAP102 (Synapse Associated Protein kDa 102) and NF-L (Neurofilament-Light), components of the PSD, were also significantly reduced with the latter reduction also found in bipolar disorder. Similarly, other studies have shown... 

Naisbitt, S., Kim, E., Tu, J. C., et al. (1999) Shank, a novel family of postsynaptic density proteins that binds to the NMDA receptor/PSD-95/GKAP complex and cortactin. Neuron 23, 569-582. 

Brenman JE, Chao DS, Gee SH, McGee AW, Craven SE, Santillano DR, Wu Z, et al. (1996) Interaction of nitric oxide synthase with the postsynaptic density protein PSD-95 and alpha 1-syntrophin mediated by PDZ domains. Cell 84 757-67 Broillet MC, Firestein S (1996) Direct activation of the olfactory cyclic nucleotide-gated channel through modification of sulfhydryl groups by NO compounds. Neuron 16 377-85... 

Fig. 2. Novel receptor-interacting partners of selected 5-HT receptors, their interaction domains on the receptors, and consequences of the interactions. Abbreviations CaM, Ca2+/calmodulin PDZ, a protein interaction domain termed postsynaptic density 95/discs large/ZO-1 PSD-95, a key protein component of the excitatory postsynaptic density MUPP1, multi-PDZ-domain protein SNX27a, a member of the new sorting nexin family of proteins NHERF, NHE regulatory factor. MUPP1 prevents phosphorylation of serine-458 of the 5-HT2C receptor.

For years, it was thought that the cytosolic carboxyl termini as well as various intracellular loops of the 5-HT receptors bind to FRAPs. Efforts from our lab to identify FRAPs utilized yeast two-hybrid screens see Fig. 1 for an overview), phage display see Fig. 2 for an overview), and direct biochemical approaches (8-13). These studies led to the discovery of many 5-HT2A receptorinteracting proteins, including caveolin-1 (Cav-1), arrestin-2 (Arr-2), arrestin-3 (Arr-3), microtubule-associated protein-1A (MAP-1A), and postsynaptic density protein-95 (PSD-95) see Table 1). 

Komau HC, Schenker LT, Kennedy MB, Seeburg PH. Domain interaction between NMDA receptor subunits and the postsynaptic density protein PSD-95. Science 1995 269 1737-1740. 

Craven SE, El-Husseini AE, Bredt DS. Synaptic targeting of the postsynaptic density protein PSD-95 mediated by lipid and protein motifs. Neuron 1999 22 497-509. 

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