Antidepressants Increase β-Arrestin2 Ubiquitinylation and Degradation by the Proteasomal Pathway in C6 Rat Glioma Cells
Abstract
beta-Arrestins, regulators of G protein-coupled receptor-G protein coupling and receptor desensitization and internalization, function also as scaffolding proteins mediating cellular signaling events. beta-Arrestin1 was previously implicated by us in the pathophysiology of depression and in the mechanism of action of antidepressants (ADs). The ubiquitously expressed beta-arrestins1 and 2 are structurally highly homologous. There has been extensive investigation of these two proteins to determine whether they serve different roles in receptor signaling. In this study, we show that treatment of C(6) rat glioma cells with ADs of various types for 3 days resulted in decreased beta-arrestin2 levels. In contrast, beta-arrestin2 mRNA expression was found to be up-regulated by ADs. To unravel the mechanism for these opposite effects several possible beta-arrestin2 post-transcriptional events and modifications were examined. C(6) rat glioma cells transfected with beta-arrestin1-targeted short hairpin RNA showed similar effects of ADs on beta-arrestin2 levels. AD-induced decreases in beta-arrestin2 protein levels were not due to cytosolic membrane translocation. Immunoprecipitation experiments showed that ADs were able to increase coimmunoprecipitation of ubiquitin with beta-arrestin2. AD-induced increases in beta-arrestin2 ubiquitinylation led to its degradation by the proteasomal pathway, as the proteasome inhibitor N-[(phenylmethoxy)carbonyl]-l-leucyl-N-[(1S)-1-formyl-3-methylbutyl]-l-leucinamide (MG-132) prevented antidepressant-induced decreases in beta-arrestin2 protein levels.
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The genes chosen for expression analysis have all recently been implicated in antidepressant drug action and neurogenesis.
“These genes were chosen because they have all recently been implicated in antidepressant drug action and neurogenesis.35, 36, 37, 38, 39, 12, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49”
From Antidepressants increase human hippocampal neurogenesis by activating the glucocorticoid receptor (2011) · cites this paper as [43]
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Antidepressants increase human hippocampal neurogenesis by activating the glucocorticoid receptor
Anacker, C., Zunszain, P. A., Cattaneo, A., Carvalho, L. A., Garabedian, M. J., Thuret, S., Price, J., & Pariante, C. M. (2011) · Molecular Psychiatry · doi:10.1038/mp.2011.26 · Cited by 435 · see citing works
- Authors
- Golan, M., Schreiber, G., & Avissar, S.
- Affiliations
- Ben-Gurion University of the Negev (IL)
- ORCID
- Golan, Moran
- Venue
- The Journal of Pharmacology and Experimental Therapeutics
- Publisher
- Elsevier BV
- Published
- 2010-03
- Volume
- 332
- Issue
- 3
- Pages
- 970-976
- ISSN
- 0022-3565 (ISSN-L)
- OpenAlex
- W2124304752
- Cited by
- 24
- References
- 41
- Citations by year
- 2024: 1 · 2021: 1 · 2020: 1 · 2019: 1 · 2018: 2 · 2017: 2 · 2016: 3 · 2015: 1 · 2014: 1 · 2013: 9
- FWCI
- 0.48
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Pharmacology and Experimental Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- β-arrestin2, antidepressants, ubiquitination, proteasomal degradation, β-arrestin1, depression, C6 glioma cells, protein stability, G protein-coupled receptor signaling, receptor desensitization, shRNA knockdown
- MeSH terms
- beta-Arrestins, beta-Arrestin 2, Animals, Antidepressive Agents, Glioma, Leupeptins, Protein Processing, Post-Translational, RNA, Messenger, Ubiquitins, Signal Transduction, Arrestins, Protein Transport, Cell Line, Tumor, Proteasome Endopeptidase Complex, Rats, Proteasome Inhibitors
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