IQ-ArfGEF/BRAG1 is a guanine nucleotide exchange factor for Arf6 that interacts with PSD-95 at postsynaptic density of excitatory synapses.
Abstract
ADP ribosylation factor 6 (Arf6) is a small GTPase that regulates dendritic differentiation possibly through the organization of actin cytoskeleton and membrane traffic. Here, we characterized IQ-ArfGEF/BRAG1, a guanine nucleotide exchange factor (GEF) for Arf6, in the mouse brain. In vivo Arf pull down assay demonstrated that IQ-ArfGEF/BRAG1 activated Arf6 more potently than Arf1. IQ-ArfGEF/BRAG1 mRNA was abundantly expressed in the brain with higher levels in forebrain structures and cerebellar granule cells. In hippocampal neurons, IQ-ArfGEF/BRAG1 mRNA was localized not only at neuronal cell bodies but also at dendritic processes, indicating its dendritic transport and localization. Immunoprecipitation and in vitro binding experiments revealed that IQ-ArfGEF/BRAG1 formed a protein complex with N-methyl-d-aspartate (NMDA)-type glutamate receptors through the interaction with a postsynaptic density (PSD) scaffold protein, PSD-95. Immunohistochemical analysis demonstrated that IQ-ArfGEF/BRAG1 was localized preferentially at the postsynaptic density of asymmetrical synapses on dendritic spines, but was lacking at GABAa receptor-carrying inhibitory synapses. Taken together, IQ-ArfGEF/BRAG1 forms a postsynaptic protein complex containing PSD-95 and NMDA receptors at excitatory synapses, where it may function as a GEF for Arf6.
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Members of the ARF family of small GTPases and their regulators are important regulators of spine density and morphology.
“Members of the ADP-ribosylation factor (ARF) family of small GTPases and their regulators have gained increasing attention as important regulators of spine density and morphology [27], [28], [29].”
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“IQSEC2 (also known as BRAG1/IQ-ArfGEF) is a neuronal ArfGEF for Arf GTPases that typically localizes to excitatory synapses as part of the NMDAR complex, via direct interaction with disks large MAGUK scaffold protein 4 (DLG4/PSD-95/SAP90; Murphy et al. 2006; Sakagami et al. 2008).”
- Authors
- Sakagami, H., Sanda, M., Fukaya, M., Miyazaki, T., Sukegawa, J., Yanagisawa, T., Suzuki, T., Fukunaga, K., Watanabe, M., & Kondo, H.
- Affiliations
- Tohoku University (JP)
- Hokkaido University (JP)
- Shinshu University (JP)
- Corresponding author
- Sakagami, Hiroyuki
- ORCID
- Venue
- Neuroscience Research
- Publisher
- Elsevier BV
- Published
- 2008-02
- Volume
- 60
- Issue
- 2
- Pages
- 199-212
- ISSN
- 0168-0102 (ISSN-L)
- OpenAlex
- W2054545874
- Cited by
- 83
- References
- 1
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 4 · 2023: 6 · 2022: 3 · 2021: 6 · 2020: 5 · 2019: 7 · 2018: 3 · 2017: 2 · 2016: 12 · 2015: 4 · 2014: 1 · 2013: 3 · 2012: 6
- FWCI
- 1.38
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neuroscience Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ministry of Education, Culture, Sports, Science and Technology
- 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 › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- ARF6, guanine nucleotide exchange factor, PSD-95, postsynaptic density, excitatory synapses, NMDA receptor, dendritic spines, dendritic transport, hippocampal neurons, cerebellar granule cells, small GTPase activation, asymmetrical synapses, inhibitory synapses
- MeSH terms
- Disks Large Homolog 4 Protein, ADP-Ribosylation Factor 6, Animals, Brain, Chlorocebus aethiops, Cloning, Molecular, Guinea Pigs, Membrane Proteins, Mice, Inbred C57BL, Neurons, Rabbits, Receptors, GABA-A, Synapses, Transfection, Receptors, N-Methyl-D-Aspartate, Gene Expression Regulation, Developmental, COS Cells, Guanine Nucleotide Exchange Factors, ADP-Ribosylation Factors, Electrophoretic Mobility Shift Assay, Immunoprecipitation, Intracellular Signaling Peptides and Proteins, Mice, Guanylate Kinases
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