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http://purl.uniprot.org/citations/17855605http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/17855605http://www.w3.org/2000/01/rdf-schema#comment"In neuronal synapses, PDZ domains [postsynaptic density-95 (PSD-95)/Discs large/zona occludens-1] of PSD-95 proteins interact with C termini of NMDA receptor [NMDAR (NR)] subunits, linking them to downstream neurotoxic signaling molecules. Perturbing NMDAR/PSD-95 interactions with a Tat peptide comprising the nine C-terminal residues of the NR2B subunit (Tat-NR2B9c) reduces neurons' vulnerability to excitotoxicity and ischemia. However, NR subunit C termini may bind many of >240 cellular PDZs, any of which could mediate neurotoxic signaling independently of PSD-95. Here, we performed a proteomic and biochemical analysis of the interactions of all known human PDZs with synaptic signaling proteins including NR1, NR2A-NR2D, and neuronal nitric oxide synthase (nNOS). Tat-NR2B9c, whose interactions define PDZs involved in neurotoxic signaling, was also used. NR2A-NR2D subunits and Tat-NR2B9c had similar, highly specific, PDZ protein interactions, of which the strongest were with the PSD-95 family members (PSD-95, PSD-93, SAP97, and SAP102) and Tax interaction protein 1 (TIP1). The PSD-95 PDZ2 domain bound NR2A-NR2C subunits most strongly (EC50, approximately 1 microM), and fusing the NR2B C terminus to Tat enhanced its affinity for PSD-95 PDZ2 by >100-fold (EC50, approximately 7 nM). IC50 values for Tat-NR2B9c inhibiting NR2A-NR2C/PSD-95 interactions (approximately 1-10 microM) and nNOS/PSD-95 interactions (200 nM) confirmed the feasibility of such inhibition. To determine which of the PDZ interactions of Tat-NR2B9c mediate neuroprotection, one of PSD-95, PSD-93, SAP97, SAP102, TIP1, or nNOS expression was inhibited in cortical neurons exposed to NMDA toxicity. Only neurons lacking PSD-95 or nNOS but not PSD-93, SAP97, SAP102, or TIP1 exhibited reduced excitotoxic vulnerability. Thus, despite the ubiquitousness of PDZ domain-containing proteins, PSD-95 and nNOS above any other PDZ proteins are keys in effecting NMDAR-dependent excitotoxicity. Consequently, PSD-95 inhibition may constitute a highly specific strategy for treating excitotoxic disorders."xsd:string
http://purl.uniprot.org/citations/17855605http://purl.org/dc/terms/identifier"doi:10.1523/jneurosci.1464-07.2007"xsd:string
http://purl.uniprot.org/citations/17855605http://purl.uniprot.org/core/author"Cui H."xsd:string
http://purl.uniprot.org/citations/17855605http://purl.uniprot.org/core/author"Phan T."xsd:string
http://purl.uniprot.org/citations/17855605http://purl.uniprot.org/core/author"Schweizer J."xsd:string
http://purl.uniprot.org/citations/17855605http://purl.uniprot.org/core/author"Hayashi A."xsd:string
http://purl.uniprot.org/citations/17855605http://purl.uniprot.org/core/author"Wang Y.T."xsd:string
http://purl.uniprot.org/citations/17855605http://purl.uniprot.org/core/author"Rabinowitz J."xsd:string
http://purl.uniprot.org/citations/17855605http://purl.uniprot.org/core/author"Salter M.W."xsd:string
http://purl.uniprot.org/citations/17855605http://purl.uniprot.org/core/author"Sun H.S."xsd:string
http://purl.uniprot.org/citations/17855605http://purl.uniprot.org/core/author"Tymianski M."xsd:string
http://purl.uniprot.org/citations/17855605http://purl.uniprot.org/core/author"Belmares M.P."xsd:string
http://purl.uniprot.org/citations/17855605http://purl.uniprot.org/core/author"Cobey C."xsd:string
http://purl.uniprot.org/citations/17855605http://purl.uniprot.org/core/author"Garman D."xsd:string
http://purl.uniprot.org/citations/17855605http://purl.uniprot.org/core/author"Lu P.S."xsd:string
http://purl.uniprot.org/citations/17855605http://purl.uniprot.org/core/author"Tasker R.A."xsd:string
http://purl.uniprot.org/citations/17855605http://purl.uniprot.org/core/date"2007"xsd:gYear
http://purl.uniprot.org/citations/17855605http://purl.uniprot.org/core/name"J Neurosci"xsd:string
http://purl.uniprot.org/citations/17855605http://purl.uniprot.org/core/pages"9901-9915"xsd:string
http://purl.uniprot.org/citations/17855605http://purl.uniprot.org/core/title"PDZ protein interactions underlying NMDA receptor-mediated excitotoxicity and neuroprotection by PSD-95 inhibitors."xsd:string
http://purl.uniprot.org/citations/17855605http://purl.uniprot.org/core/volume"27"xsd:string
http://purl.uniprot.org/citations/17855605http://www.w3.org/2004/02/skos/core#exactMatchhttp://purl.uniprot.org/pubmed/17855605
http://purl.uniprot.org/citations/17855605http://xmlns.com/foaf/0.1/primaryTopicOfhttps://pubmed.ncbi.nlm.nih.gov/17855605
http://purl.uniprot.org/uniprot/#_Q13224-mappedCitation-17855605http://www.w3.org/1999/02/22-rdf-syntax-ns#objecthttp://purl.uniprot.org/citations/17855605
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