ArticleProceedings of the National Academy of Sciences of the United States of America2016
PSD-95 stabilizes NMDA receptors by inducing the degradation of STEP61.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 79 papers.
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Who cites it
79 citing papers in PubMed.
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- Effects of the STriatal Enriched Tyrosine Phosphatase (STEP) Inhibitor TC-2153 on Hippocampal Long-Term Depression and Synaptic Transmission: Paradoxical Effect on Phosphatase Activity and Role of Adenosine.CNS neuroscience & therapeutics · 2026Article
- Localization and Functional Characterization of MDGA1 in Mouse Hippocampus.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2026Article
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- A synapse-specific refractory period for plasticity at individual dendritic spines.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
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- Mitigation of synaptic and memory impairments via F-actin stabilization in Alzheimer's disease.Alzheimer's research & therapy · 2024Article
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- The Left-Right Side-Specific Neuroendocrine Signaling from Injured Brain: An Organizational Principle.Function (Oxford, England) · 2024Article
- Trans-synaptic Association of Vesicular Zinc Transporter 3 and Shank3 Supports Synapse-Specific Dendritic Spine Structure and Function in the Mouse Auditory Cortex.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2024Article
- Chronic intermittent hypoxia induces cognitive impairment in Alzheimer's disease mouse model via postsynaptic mechanisms.Sleep & breathing = Schlaf & Atmung · 2024Article
19 more citing papers are in PubMed but not listed here.
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Authors and funding
4 authors.
Funding
Abstract
Phosphorylation regulates surface and synaptic expression of NMDA receptors (NMDARs). Both the tyrosine kinase Fyn and the tyrosine phosphatase striatal-enriched protein tyrosine phosphatase (STEP) are known to target the NMDA receptor subunit GluN2B on tyrosine 1472, which is a critical residue that mediates NMDAR endocytosis. STEP reduces the surface expression of NMDARs by promoting dephosphorylation of GluN2B Y1472, whereas the synaptic scaffolding protein postsynaptic density protein 95 (PSD-95) stabilizes the surface expression of NMDARs. However, nothing is known about a potential functional interaction between STEP and PSD-95. We now report that STEP61 binds to PSD-95 but not to other PSD-95 family members. We find that PSD-95 expression destabilizes STEP61 via ubiquitination and degradation by the proteasome. Using subcellular fractionation, we detect low amounts of STEP61 in the PSD fraction. However, STEP61 expression in the PSD is increased upon knockdown of PSD-95 or in vivo as detected in PSD-95-KO mice, demonstrating that PSD-95 excludes STEP61 from the PSD. Importantly, only extrasynaptic NMDAR expression and currents were increased upon STEP knockdown, as is consistent with low STEP61 localization in the PSD. Our findings support a dual role for PSD-95 in stabilizing synaptic NMDARs by binding directly to GluN2B but also by promoting synaptic exclusion and degradation of the negative regulator STEP61.
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