Regulation of STEP61 and tyrosine-phosphorylation of NMDA and AMPA receptors during homeostatic synaptic plasticity
Open accessAbstract
BACKGROUND: Sustained changes in network activity cause homeostatic synaptic plasticity in part by altering the postsynaptic accumulation of N-methyl-D-aspartate receptors (NMDAR) and α-amino-3-hydroxyle-5-methyl-4-isoxazolepropionic acid receptors (AMPAR), which are primary mediators of excitatory synaptic transmission. A key trafficking modulator of NMDAR and AMPAR is STriatal-Enriched protein tyrosine Phosphatase (STEP61) that opposes synaptic strengthening through dephosphorylation of NMDAR subunit GluN2B and AMPAR subunit GluA2. However, the role of STEP61 in homeostatic synaptic plasticity is unknown. FINDINGS: We demonstrate here that prolonged activity blockade leads to synaptic scaling, and a concurrent decrease in STEP61 level and activity in rat dissociated hippocampal cultured neurons. Consistent with STEP61 reduction, prolonged activity blockade enhances the tyrosine phosphorylation of GluN2B and GluA2 whereas increasing STEP61 activity blocks this regulation and synaptic scaling. Conversely, prolonged activity enhancement increases STEP61 level and activity, and reduces the tyrosine phosphorylation and level of GluN2B as well as GluA2 expression in a STEP61-dependent manner. CONCLUSIONS: Given that STEP61-mediated dephosphorylation of GluN2B and GluA2 leads to their internalization, our results collectively suggest that activity-dependent regulation of STEP61 and its substrates GluN2B and GluA2 may contribute to homeostatic stabilization of excitatory synapses.
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Scaling-up appears to involve increased tyrosine phosphorylation of GluA2 as a result of downregulation of the tyrosine phosphatase STEP61, and scaling-up could be blocked by exogenously applied STEP61.
“Scaling-up appears to involve increased tyrosine phosphorylation of GluA2 as a result of downregulation of the tyrosine phosphatase, STEP61 (Figure 3), and scaling-up could be blocked by exogenously applied STEP61 (Jang et al., 2015).”
From The AMPA Receptor Code of Synaptic Plasticity (2018) · cites this paper as Jang et al., 2015
The Results and discussion report that activity blockade reduced STEP61 and increased GluA2 tyrosine phosphorylation, and that TAT-STEP WT preincubation abolished TTX-induced synaptic scaling. However, the applied TAT-STEP protein was a STEP46 fusion, not exogenously applied STEP61 as the claim specifies. Page numbers were not provided in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredDephosphorylation of GluA2 S880 during scaling-down is mediated by activation of phosphatase PP1 through its regulatory protein inhibitor 2 (I-2), while dephosphorylation of GluA2 Y876 requires an upregulation of STEP61.
“Dephosphorylation of GluA2 S880 during scaling-down is mediated by activation of phosphatase PP1, through its regulatory protein inhibitor 2 (I-2) (Siddoway et al., 2013), while dephosphorylation of GluA2 Y876 requires an upregulation of STEP61 (Jang et al., 2015).”
From The AMPA Receptor Code of Synaptic Plasticity (2018) · cites this paper as Jang et al., 2015
The Jang citation attaches to the STEP61/GluA2 Y876 clause, not the PP1/I-2 clause. In Results and discussion (page not supplied), increased STEP61 coincided with reduced phosphorylation of GluA2 at a three-tyrosine site that includes Y876. The authors say the specific GluA2 tyrosine residues regulated by STEP61 are unknown, and inhibiting STEP did not block the measured reduction in three-tyrosine phosphorylation; the paper therefore does not establish that Y876 dephosphorylation requires STEP61 upregulation. (LLM, conf=0.88)
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Cited by
Sorted by citations
The AMPA Receptor Code of Synaptic Plasticity
Diering, G. H., & Huganir, R. L. (2018) · Neuron · doi:10.1016/j.neuron.2018.10.018 · Cited by 844 · see citing works
Wang, G., An, T., Lei, C., Zhu, X., Yang, L., Zhang, L., & Zhang, R. (2022) · Journal of Ginseng Research · doi:10.1016/j.jgr.2021.03.005 · Cited by 101 · see citing works
- Authors
- Jang, S.-S., Royston, S. E., Xu, J., Cavaretta, J. P., Vest, M. O., Lee, K. Y., Lee, S., Jeong, H. G., Lombroso, P. J., & Chung, H. J.
- Affiliations
- University of Illinois Urbana-Champaign (US)
- Yale University (US)
- Corresponding author
- Chung, Hee Jung
- Venue
- Molecular Brain
- Published
- 2015-09-22
- Volume
- 8
- Issue
- 1
- Pages
- 55-55
- ISSN
- 1756-6606 (ISSN-L)
- PMC
- PMC4578242
- OpenAlex
- W1899812921
- Cited by
- 45
- References
- 4
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 1 · 2023: 6 · 2022: 3 · 2021: 4 · 2020: 6 · 2019: 4 · 2018: 5 · 2017: 3 · 2016: 9
- FWCI
- 2.64
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Molecular Brain (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- ICR start-up fund, Office of the Vice Chancellor for Research, University of Illinois at Urbana-Champaign
- Epilepsy Foundation Predoctoral Fellowship (C4855)
- National Institutes of Health (MH052711, MH091037)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Keywords
- protein tyrosine phosphatase, homeostatic plasticity, synaptic scaling, NMDA receptor, AMPA receptors, GluN2B, GluA2, tyrosine phosphorylation, receptor dephosphorylation, excitatory synapses, activity-dependent regulation, hippocampal neurons, synaptic homeostasis
- MeSH terms
- Animals, Homeostasis, Models, Biological, Nerve Net, Neuronal Plasticity, Phosphorylation, Receptors, N-Methyl-D-Aspartate, Protein Tyrosine Phosphatases, Rats, Sprague-Dawley, Receptors, AMPA, Phosphotyrosine
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