PDZ Protein Interactions Regulating Glutamate Receptor Function and Plasticity

Neurotransmission occurs at synapses, specialized points of contact between presynaptic nerve terminals and postsynaptic neurons. At excitatory synapses, receptors and downstream signaling enzymes are clustered in the postsynaptic density (PSD), 1 a cytoskeletal web beneath the plasma membrane. Transmission at these excitatory synapses is mediated primarily by glutamate acting on two classes of ligand-gated ion channels: AMPA receptors and NMDA receptors. The AMPA receptors are involved in moment-to-moment signaling, whereas NMDA receptors play an important role in initiating synaptic plasticity. Recent cell biological analyses have emphasized remarkable differences in regulation of the synaptic expression of these two classes of receptors (Malenka and Nicoll, 1999; Malinow et al., 2000). NMDA receptors are stable components of the PSD, whereas AMPA receptors cycle on and off the synaptic membrane in a manner that is tightly controlled by neuronal activity (Lüscher et al., 1999; Beattie et al., 2000; Ehlers, 2000; Lin et al., 2000). Regulated insertion and removal of AMPA receptors at the synapse provides a mechanism for altering synaptic efficacy, and for storing information in the brain (Malenka and Nicoll, 1999; Malinow et al., 2000). This has lead to intensive study of the molecular architecture that recruits and anchors glutamate receptors at the synapse. A key breakthrough in understanding mechanisms for synapse assembly came from the discovery that proteins containing PSD-95/SAP-90, Discs-large, ZO-1 homologous domian (PDZ) motifs play central roles in scaffolding receptors and signaling elements (Kennedy, 1997; Craven and Bredt, 1998; Hsueh and Sheng, 1998; Garner et al., 2000). The prototypical PDZ protein, PSD-95, is a membraneassociated guanylate kinase (MAGUK) that contains three PDZ domains and associates with NMDA receptors at the synapse. Three other neuronal MAGUKs, PSD-93, synapse-associated protein (SAP)-97, and SAP-102, are also expressed in neurons throughout the brain. The first and second PDZ domains of PSD-95, and the other neuronal MAGUKs, bind to the extreme COOH termini of NMDA receptor subunits and certain other proteins that terminate with a Ser/Thr-X-Val motif. In addition, the second PDZ domain from PSD-95 binds to a PDZ domain at the NH 2 terminus of neuronal nitric oxide synthase (Brenman et al., 1996). By bridging the NMDA receptor to neuronal nitric oxide synthase, PSD-95 functions as a scaffold to enhance activation of calmodulin-dependent neuronal nitric oxide synthase activity by Ca 2 influx through the NMDA receptor (Sattler et al., 1999).