Determinants of synaptic specificity in the brain

The transmission of signals between neurons in the brain occurs at specialized areas of contact called synapses. The precise organization of synaptic proteins is essential for efficient synaptic transmission. For example, neurotransmitter receptors and other proteins involved in signal transduction are highly concentrated at synaptic contacts. Recently a large family of proteins that contain protein-protein interaction motifs called PDZ domains have been suggested to be involved in the organization of synaptic structure. We have identified a novel PDZ domain containing protein, GRIP, that interacts with AMPA receptors, major excitatory neurotransmitter receptors in the brain. GRIP appears to serve as an adaptor protein which links AMPA receptors to other proteins involved in signal transduction or receptor localization. We are currently characterizing several novel proteins called GRASPs (GRIP associated proteins) that selectively bind to various PDZ domains of GRIP and may regulate synaptic function. We have also been analyzing the role of the PSD95/SAP90 family of PDZ domain containing proteins in the regulation of NMDA receptor function. NMDA receptors are major excitatory receptors in brain that are critical for learning and memory. We have identified a novel synapse specific ras-GAP, GAPSYN, that associates with the PSD95/SAP90 protein and NMDA receptors at synapses. GAPSYN appears to play a specific role in the regulation of ras signaling at excitatory synapses. These results suggest that synaptic specificity may in part be defined by PDZ domain containing proteins which associate with neurotransmitter receptors and other proteins involved in receptor localization and downstream signal transduction.