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NMDA receptor desensitization regulated by direct binding to PDZ1-2 domains of PSD-95 Sornarajah, Lavan

Abstract

Regulation of NMDA 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) domains 1 and 2 of PSD-95 bind to the C-terminus of NMDAR NR2 subunits. The role of PSD-95 in anchoring signaling proteins in close proximity to NMDARs is well documented. To determine if changes in NMDAR desensitization occur because of the direct binding of PSD-95 to NMDARs or due to PSD-95 recruitment of regulatory molecules, 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 markedly reduced NMDAR desensitization, and the N-terminus of PSD- 95 truncated after the PDZ 1-2 domains was sufficient for this effect even when multimerization of PSD-95 was abolished. In immature neurons where PSD-95 expression is low, overexpression of either PSD-95 or PSD-95 PDZ 1-2 was sufficient to significantly decrease 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 direct regulation of NMDAR activity by PKC. We conclude that direct binding of PSD-95 increases stability of NMDAR responses to sustained agonist exposure in neuronal and non-neuronal cells.

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