The novel caspase-3 substrate Gap43 is involved in AMPA receptor endocytosis and long-term depression
Open accessAbstract
The cysteine protease caspase-3, best known as an executioner of cell death in apoptosis, also plays a non-apoptotic role in N-methyl-d-aspartate receptor-dependent long-term depression of synaptic transmission (NMDAR-LTD) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor endocytosis in neurons. The mechanism by which caspase-3 regulates LTD and AMPA receptor endocytosis, however, remains unclear. Here, we addressed this question by using an enzymatic N-terminal peptide enrichment method and mass spectrometry to identify caspase-3 substrates in neurons. Of the many candidates revealed by this proteomic study, we have confirmed BASP1, Dbn1, and Gap43 as true caspase-3 substrates. Moreover, in hippocampal neurons, Gap43 mutants deficient in caspase-3 cleavage inhibit AMPA receptor endocytosis and LTD. We further demonstrated that Gap43, a protein well-known for its functions in axons, is also localized at postsynaptic sites. Our study has identified Gap43 as a key caspase-3 substrate involved in LTD and AMPA receptor endocytosis, uncovered a novel postsynaptic function for Gap43 and provided new insights into how long-term synaptic depression is induced.
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GAP-43 is down-regulated in PSD with mTORC1 inhibition.
“We selected GAP-43 protein as a control that is down-regulated in PSD with mTORC1 inhibition (79).”
From Analysis of proteins that rapidly change upon mechanistic/mammalian target of rapamycin complex 1 (mTORC1) repression identifies parkinson protein 7 (PARK7) as a novel protein aberrantly expressed in tuberous sclerosis complex (TSC) (2016) · cites this paper as [79]
The section ‘Gap43 is Localized at the Postsynaptic Site’ reports that Gap43 was detected in the postsynaptic density (PSD) fraction. It does not report that mTORC1 inhibition down-regulates Gap43 there; searches for mTORC1 inhibition and rapamycin found no supporting passage in our copy. (LLM, conf=0.83)
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Regulation of AMPA receptor endocytosis by a signaling mechanism shared with LTD
Beattie, E. C., Carroll, R. C., Yu, X., Morishita, W., Yasuda, H., von Zastrow, M., & Malenka, R. C. (2000) · Nature Neuroscience · doi:10.1038/81823 · Cited by 745 · see citing works
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Niere, F., Namjoshi, S., Song, E., Dilly, G. A., Schoenhard, G., Zemelman, B. V., Mechref, Y., & Raab-Graham, K. F. (2016) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m115.055079 · Cited by 38 · see citing works
“We selected GAP-43 protein as a control that is down-regulated in PSD with mTORC1 inhibition (79).”
Background
- Authors
- Han, M.-H., Jiao, S., Jia, J.-M., Chen, Y., Chen, C. Y., Gucek, M., Markey, S. P., & Li, Z.
- Affiliations
- National Institute of Mental Health (US)
- National Heart, Lung, and Blood Institute (US)
- Corresponding author
- Li, Zheng
- Venue
- Molecular & Cellular Proteomics
- Publisher
- Elsevier BV
- Published
- 2013-12
- Volume
- 12
- Issue
- 12
- Pages
- 3719-3731
- ISSN
- 1535-9476 (ISSN-L)
- PMC
- PMC3861719
- OpenAlex
- W2124551632
- Cited by
- 62
- References
- 1
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 7 · 2023: 4 · 2022: 6 · 2021: 4 · 2020: 6 · 2019: 3 · 2018: 4 · 2017: 6 · 2016: 6 · 2015: 6 · 2014: 4
- FWCI
- 2.62
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular & Cellular Proteomics (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- U.S. Public Health Service (1ZIAMH00279-27, 1ZIAMH002881, 1ZIAMH000274-35)
- National Institute of Mental Health (1ZIAMH00279-27, ZIAMH000274, ZIAMH002881, ZIAMH000279)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- caspase-3, GAP-43, AMPA receptor endocytosis, long-term depression, NMDA receptor, BASP1, postsynaptic function, hippocampal neurons, synaptic plasticity, non-apoptotic caspase function
- MeSH terms
- Animals, Embryo, Mammalian, Endocytosis, Hippocampus, Synaptic Transmission, Neuronal Plasticity, Neurons, Protein Binding, Synapses, Receptors, N-Methyl-D-Aspartate, Rats, Sprague-Dawley, Receptors, AMPA, Patch-Clamp Techniques, Gene Expression Regulation, Developmental, GAP-43 Protein, Protein Interaction Mapping, Long-Term Synaptic Depression, Tissue Culture Techniques, Rats, Caspase 3, Primary Cell Culture
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