GRIP1 and 2 regulate activity-dependent AMPA receptor recycling via exocyst complex interactions
Open accessAbstract
PSD-95/SAP90/DLG/ZO-1 (PDZ) domain-mediated protein–protein interactions play important roles in regulating AMPA receptor trafficking and neuronal plasticity. GRIP1 and GRIP2 are homologous multi-PDZ domain-containing proteins that bind to the C-termini of AMPA-R GluA2 and GluA3 subunits. Previous attempts to determine the cellular roles of GRIP1 and GRIP2 in neurons have been complicated by nonspecific reagents, and by the embryonic lethality of conventional GRIP1 KO mice. To circumvent these issues we developed a conditional targeted deletion strategy to knock out GRIP1 in postnatal neurons derived from GRIP2 KO mice. Loss of GRIP1 and 2 did not affect normal AMPA-R steady-state trafficking and endocytosis, but strikingly impaired activity-dependent AMPA-R recycling. This previously uncharacterized role for GRIP1 appears to be mediated by novel interactions with the cellular trafficking machinery via the exocyst protein complex. Indeed, disruption of GRIP1-exocyst binding caused a strikingly similar deficit in AMPA-R recycling. Together these findings reveal a previously unidentified role for AMPA-R-GRIP1-exocyst protein complexes in activity-dependent AMPA-R trafficking.
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Exocyst-mediated AMPA receptor targeting, insertion, and recycling are thought to be independent of Ral.
“exocystmediated AMPA receptor targeting, insertion, and recycling (Sans et al, 2003;Gerges et al, 2006;Mao et al, 2010) are thought to be independent of Ral.”
From Ral mediates activity‐dependent growth of postsynaptic membranes via recruitment of the exocyst (2013) · cites this paper as Mao et al, 2010
The Discussion reports exocyst involvement in AMPA receptor transport, synaptic accumulation, and recycling, supporting that part of the attribution. It does not address Ral or say that these processes are independent of Ral (searched: Ral, Ral-independent exocyst trafficking). Page numbers are unavailable in our copy. (LLM, conf=0.86)
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AMPA Receptor Trafficking and Synaptic Plasticity
Malinow, R., & Malenka, R. C. (2002) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.25.112701.142758 · Cited by 2,588 · see citing works
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
NMDA receptor trafficking through an interaction between PDZ proteins and the exocyst complex
Sans, N., Prybylowski, K., Petralia, R. S., Chang, K., Wang, Y.-X., Racca, C., Vicini, S., & Wenthold, R. J. (2003) · Nature Cell Biology · doi:10.1038/ncb990 · Cited by 327 · see citing works
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Assembly of functionally integrated human forebrain spheroids
Birey, F., Andersen, J., Makinson, C. D., Islam, S., Wei, W., Huber, N., Fan, H. C., Metzler, K. R. C., Panagiotakos, G., Thom, N., et al. (2017) · Nature · doi:10.1038/nature22330 · Cited by 1,365 · see citing works
Regulation of AMPA receptor trafficking and synaptic plasticity
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Self-citationGRIP1 is required for homeostatic regulation of AMPAR trafficking
Tan, H. L., Queenan, B. N., & Huganir, R. L. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1512786112 · Cited by 69 · see citing works
Self-citationRal mediates activity‐dependent growth of postsynaptic membranes via recruitment of the exocyst
Teodoro, R. O., Pekkurnaz, G., Nasser, A., Higashi‐Kovtun, M. E., Balakireva, M., McLachlan, I. G., Camonis, J., & Schwarz, T. L. (2013) · The EMBO Journal · doi:10.1038/emboj.2013.147 · Cited by 61 · see citing works
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Murphy, K. M., Tcharnaia, L., Beshara, S. P., & Jones, D. G. (2012) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2012.00065 · Cited by 20 · see citing works
- Authors
- Mao, L., Takamiya, K., Thomas, G., Lin, D.-T., & Huganir, R. L.
- Affiliations
- Howard Hughes Medical Institute (US)
- University of Miyazaki (JP)
- Corresponding author
- Huganir, Richard L.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2010-10-18
- Volume
- 107
- Issue
- 44
- Pages
- 19038-19043
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2973854
- OpenAlex
- W2083734198
- Cited by
- 94
- References
- 4
- Citations by year
- 2026: 6 · 2025: 7 · 2024: 10 · 2023: 4 · 2022: 9 · 2021: 3 · 2020: 7 · 2019: 5 · 2018: 1 · 2017: 7 · 2016: 1 · 2015: 7 · 2014: 5 · 2013: 7 · 2012: 8
- FWCI
- 2.56
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (R01NS036715)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- GRIP1, exocyst complex, GluA2, GluA3, synaptic plasticity, conditional knockout, postnatal neurons, receptor internalization
- MeSH terms
- Animals, Carrier Proteins, Exocytosis, Humans, Nerve Tissue Proteins, Neurons, Receptors, AMPA, Protein Transport, Intercellular Signaling Peptides and Proteins, Intracellular Signaling Peptides and Proteins, Adaptor Proteins, Signal Transducing, Mice, Rats, HEK293 Cells
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