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• W2003163064 abstract "Regulation of N-methyl-d-aspartate receptor (NMDAR) activity by desensitization is important in physiological and pathological states; NMDAR desensitization contributes in shaping synaptic responses and may be protective by limiting calcium influx during sustained glutamate insults. We previously reported that glycine-independent desensitization decreases during hippocampal neuronal development, correlating with NMDAR synaptic localization and association with postsynaptic density 95 (PSD-95). PSD-95/Discs large/zona occludens (PDZ)-1,2 domains of PSD-95 bind to the C-terminus of NMDAR NR2 subunits. The role of PSD-95 in anchoring signaling proteins near NMDARs is well documented. To determine if PSD-95-induced changes in NMDAR desensitization occur because of direct binding to NR2 or due to recruitment of regulatory proteins, we tested the effects of various PSD-95 constructs on NMDAR currents in human embryonic kidney 293 (HEK293) cells and neurons. In HEK cells, wild-type PSD-95 significantly reduced wild-type NMDAR desensitization without altering currents of NMDARs containing NR2A-S1462A, a mutation that abolishes PSD-95 binding. The PSD-95 N-terminus truncated after the PDZ1-2 domains was sufficient for this effect in neurons with low endogenous PSD-95 levels; in NMDAR-expressing HEK cells, the effect persisted when PSD-95 multimerization was eliminated. Moreover other PSD-95 family members with highly homologous PDZ1-2 domains significantly reduced NMDAR desensitization. In mature neurons, disruption of PSD-95/NMDAR interaction through protein kinase C (PKC) activation increased desensitization to levels found in immature neurons, and this effect was not due to PKC direct regulation of NMDAR activity. We conclude that direct binding of PSD-95 increases stability of NMDAR responses to agonist exposure in neuronal and nonneuronal cells." @default.
• W2003163064 created "2016-06-24" @default.
• W2003163064 creator A5020418567 @default.
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• W2003163064 date "2008-06-01" @default.
• W2003163064 modified "2023-09-30" @default.
• W2003163064 title "NMDA Receptor Desensitization Regulated by Direct Binding to PDZ1-2 Domains of PSD-95" @default.
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• W2003163064 doi "https://doi.org/10.1152/jn.90301.2008" @default.
• W2003163064 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/3013345" @default.
• W2003163064 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/18400955" @default.
• W2003163064 hasPublicationYear "2008" @default.
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