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Phosphorylation of Rpt6 Regulates Synaptic Strength in Hippocampal Neurons
Open accessAbstract
It has become increasingly evident that protein degradation via the ubiquitin proteasome system plays a fundamental role in the development, maintenance and remodeling of synaptic connections in the CNS. We and others have recently described the activity-dependent regulation of proteasome activity and recruitment of proteasomes into spine compartments involving the phosphorylation of the 19S ATPase subunit, Rpt6, by the plasticity kinase Ca 2+/calmodulin-dependent protein kinase II α (CaMKIIα) (Bingol and Schuman, 2006; Djakovic et al., 2009; Bingol et al, 2010). Here, we investigated the role of Rpt6 phosphorylation on proteasome function and synaptic strength. Utilizing a phospho-specific antibody we verified that Rpt6 is phosphorylated at Serine 120 (S120) by CaMKIIα. In addition, we found that Rpt6 is phosphorylated by CaMKIIα in an activity-dependent manner. Furthermore, we showed that a serine 120 to aspartic acid phospho-mimetic mutant of Rpt6 (S120D) increases its resistance to detergent extraction in rat hippocampal dendrites, indicating phosphorylated Rpt6 may promote the tethering of proteasomes to scaffolds and cytoskeletal components. Expression of Rpt6 S120D decreased miniature EPSC (mEPSC) amplitude, while expression of a phospho-dead mutant (S120A) increased mEPSC amplitude. Surprisingly, homeostatic scaling of mEPSC amplitude produced by chronic application of bicuculline or tetrodotoxin is both mimicked and occluded by altered Rpt6 phosphorylation. Together, these data suggest that CaMKII-dependent phosphorylation of Rpt6 at S120 may be an important regulatory mechanism for proteasome-dependent control of synaptic remodeling in slow homeostatic plasticity.
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“We have previously shown that Rpt6 is involved in the regulation of synaptic strength and activity-dependent generation of new spines (Djakovic et al., 2012; Hamilton et al., 2012).”
From Proteasome phosphorylation regulates cocaine-induced sensitization (2018) · cites this paper as Djakovic et al., 2012
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“In subsequent in vitro investigations, we showed that homeostatic scaling of synaptic strength induced by chronic changes in synaptic activity is impaired by altered Rpt6 S120 phosphorylation (Djakovic et al., 2012).”
From Altered Phosphorylation of the Proteasome Subunit Rpt6 Has Minimal Impact on Synaptic Plasticity and Learning (2021) · cites this paper as Djakovic et al., 2012
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“In further investigations, we showed that homeostatic scaling of synaptic strength induced by chronic application of bicuculline or tetrodotoxin is both mimicked and occluded by altered Rpt6 phosphorylation (Djakovic et al., 2012).”
From Altered Phosphorylation of the Proteasome Subunit Rpt6 Has Minimal Impact on Synaptic Plasticity and Learning (2021) · cites this paper as Djakovic et al., 2012
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“We previously reported using ectopically expressed S120 mutants suggested that proteasome distribution in dendrites is affected by the phospho-status of Rpt6 (Djakovic et al., 2012).”
From Altered Phosphorylation of the Proteasome Subunit Rpt6 Has Minimal Impact on Synaptic Plasticity and Learning (2021) · cites this paper as Djakovic et al., 2012
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“We found that our custom pS120 phospho-speci fi c antibody, which does not recognize Rpt6 S120A mutant protein (Djakovic et al., 2012) and slightly cross reacts with the Rpt6 S120D which is likely due to the negative charge of the aspartic acid residue (Fig. 2D).”
From Proteasome phosphorylation regulates cocaine-induced sensitization (2018) · cites this paper as Djakovic et al., 2012
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“CaMKII α phosphorylates the ATPase 19S (RP) subunit of the 26S proteasome, Rpt6, at serine 120 (S120) in an activity-dependent fashion to control the activity and distribution of proteasomes in neurons (Djakovic et al., 2009; Bingol et al., 2010; Djakovic et al., 2012).”
From Proteasome phosphorylation regulates cocaine-induced sensitization (2018) · cites this paper as Djakovic et al., 2012
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“Phosphorylation of the 19S ATPase subunit Rpt6 at S120 has been shown to be regulated by CaMKII α in an activity-dependent manner”
From Proteasome phosphorylation regulates cocaine-induced sensitization (2018) · cites this paper as Djakovic et al., 2012
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“and increases in Rpt6 S120 phosphorylation correlated with increased proteasome activity (Figs. 1 and 3; Djakovic et al., 2012).”
From Proteasome phosphorylation regulates cocaine-induced sensitization (2018) · cites this paper as Djakovic et al., 2012
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Citations
Cites
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Activity level controls postsynaptic composition and signaling via the ubiquitin-proteasome system
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Synaptic Protein Degradation Underlies Destabilization of Retrieved Fear Memory
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Autophosphorylated CaMKIIα Acts as a Scaffold to Recruit Proteasomes to Dendritic Spines
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Regulation of the proteasome by neuronal activity and calcium/calmodulin-dependent protein kinase II
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“…coverslips or glass bottom 35 mm dishes (hippocampal cultures) (Mattek) or poly-D-lysine-coated 6-well dishes at 500,000 cells per well (cortical cultures) and were maintained in B27 supplemented Neurobasal media (Invitrogen) until 14 d, as previously described (Djakovic et al., 2009).”
BackgroundMethodInfluentialSelf-citationEmerging Roles for Ubiquitin and Protein Degradation in Neuronal Function
Yi, J. J., & Ehlers, M. D. (2007) · Pharmacological Reviews · doi:10.1124/pr.59.1.4 · Cited by 224
Catalytic Mechanism and Assembly of the Proteasome
Marques, A. J., Palanimurugan, R., Matias, A. C., Ramos, P. C., & Dohmen, R. J. (2009) · Chemical Reviews · doi:10.1021/cr8004857 · Cited by 181
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The Effects of Aging on Proteasome Activity, Assembly, and Abundance in C. elegans
Joyce, D. (2012) · eScholarship (California Digital Library)
Ubitquitin Proteasome System, Protein Degradation, and Memory
Jarome, T. J., & Helmstetter, F. J. (2017) · Elsevier eBooks · doi:10.1016/b978-0-12-809324-5.21121-8
Roles of CaMKII in Learning and Memory ☆
Stephenson, J. R., & Colbran, R. J. (2017) · Elsevier eBooks · doi:10.1016/b978-0-12-809324-5.21106-1
Seabra, G. (2019) · LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas)
Thibaudeau, T. A. (2019) · The Research Repository @ WVU (West Virginia University) · doi:10.33915/etd.3780
Vergara, P., Pino, G., Vera, J., & Sanhueza, M. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.11.09.467941
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The proteasome interactome and its role in the mechanisms of brain plasticity
Бунеева, О. А., Kopylov, A. T., & Medvedev, A. E. (2023) · Biochemistry (Moscow) · doi:10.31857/s032097252303003x
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Jarome, T. J. (2013) · UWM Digital Commons (University of Wisconsin–Milwaukee)
Metadata
- Authors
- Djakovic, S. N., Marquez-Lona, E. M., Jakawich, S. K., Wright, R., Chu, C., Sutton, M. A., & Patrick, G. N.
- Affiliations
- University of California San Diego (US)
- University of Michigan (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2012-04-11
- Volume
- 32
- Issue
- 15
- Pages
- 5126-5131
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3348785
- OpenAlex
- W2119458938
- Semantic Scholar
- 86582538729c803453ab2a57d94f3b35a47a4c59
- Cited by
- 112
- References
- 17
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 2 · 2023: 5 · 2022: 10 · 2021: 10 · 2020: 7 · 2019: 11 · 2018: 10 · 2017: 13 · 2016: 8 · 2015: 10 · 2014: 8 · 2013: 12 · 2012: 3
- FWCI
- 4.35
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- U.S. Public Health Service (P50-GMO85764)
- National Institute of Mental Health (MH085798, R01MH085798)
- National Institute of General Medical Sciences (P50GM085764)
- National Institute of Neurological Disorders and Stroke (R21NS054732, R01NS060847, NS054732, NS060847)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- CaMKIIα, ubiquitin-proteasome system, synaptic plasticity, miniature EPSCs, hippocampal neurons, synaptic remodeling
- MeSH terms
- ATPases Associated with Diverse Cellular Activities, Animals, Bicuculline, Carrier Proteins, Cells, Cultured, Dendrites, DNA, Hippocampus, Humans, Neuronal Plasticity, Neurons, Phosphorylation, Serine, Synapses, Tetrodotoxin, Microscopy, Confocal, GABA Antagonists, Excitatory Postsynaptic Potentials, Proteasome Endopeptidase Complex, Immunoprecipitation, Rats, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Electrophysiological Phenomena
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