Synaptic junctions are highly specialized sites of cell-cell contact that are involved in the rapid regulated transfer of information between neurons and their targets. At present little is known concerning the molecular mechanisms regulating the site specific assembly of different synaptic types. Theoretically, the specificity could arise through the selective recruitment of specific membrane cytoskeletal proteins at the site of neuron-target contact which in turn act to cluster the appropriate ion channels and neurotransmitter receptors. As a direct result of our efforts to identify novel constituents of we have isolated cDNA clones encoding a novel family of structurally related Synapse-Associated Proteins (SAPs). Of the 10 or so members of this family expressed in rat brain, we have cloned and characterized 3 called SAP90, SAP97 and SAP102. Immunoelectron microscopic studies have shown that SAP90 is localized in presynaptic nerve terminals of GABAergic synapses, SAP97 ina the presynaptic nerve terminals of asymmetric synapses and SAP102 in the postsynaptic density an dendritic spines of asymmetric dendro spiny synapses. Recent studies show that domains within these proteins bind and cluster ion channels and neurotransmitter receptors. The ability of SAPs to also bind cortical membrane cytoskeleton in a calcium/cadherin dependent manner suggest that they may be involve in anchoring receptors an channels in synaptic junctions. SAP90. SAP97 and SAP102 are structurally related to the product of a Drosophila tumor suppressor gene dig-1. The protein product D1g-A has been localized at the larvae body wall neuromuscular junction and at septate junctions between epithelial cells and in Drosophila. Homozygous mutants in dlg are larval lethal and cause a tumorous overgrowth of th central nervous system and the imaginal discs. SAPs/D1gA are mosaic proteins composed of three domains i) domains that bind integral membrane protein an the cortical cytoskeleton, ii) an SH3 domain and iii) a C- terminal domain with striking homology to low molecular weight guanylate kinases. In this application, we propose to study the function role of SAP102 in the formation and function of synaptic junctions. Specifically, we will investigate the molecular interaction between SAP102 and subunits of the NMDA receptors and the role the GK domain in SAP102 plays in the clustering of these receptors and the assembly and function of synaptic junctions.
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