Modulation of actin dynamics by Rac1 to target cognitive function
Open accessAbstract
The small GTPase Rac1 is well known for regulating actin cytoskeleton reorganization in cells. Formation of extensions at the surface of the cell is required for migration and even for cell invasion and metastases. Because an elevated level and hyperactivation of this protein has been associated with metastasis in cancer, direct regulators of Rac1 are currently envisioned as a potential strategy to treat certain cancers. Less research, however, has been done regarding the role of this small GTP-binding protein in brain development, where it has an important role in dendritic spine morphogenesis through the regulation of actin. Alteration of dendritic development and spinogenesis has been often associated with mental disorders. Rac1 is associated with and required for learning and the formation of memories in the brain. Rac1 appears to be dysregulated in certain neurodevelopmental disorders that present all these three alterations: mental retardation, atypical synaptic plasticity and aberrant spine morphology. Thus, to develop novel therapies for rescuing cognitive impairment, a reasonable approach might be to target this protein, Rac1, which plays a pivotal role in directing signals that regulate actin dynamics, which in turn might have an effect in spine cytoarchitecture and synaptic function. It is possible that novel drugs that regulate Rac1 activation and function could modulate actin cytoskeleton and spine dynamics, representing potential candidates to repair intellectual disability in disorders associated with spine abnormalities. Herein, we present a list of the current Rac1 inhibitors that might fulfill this role together with a summary of the latest findings concerning their function as they relate to neuronal studies. While the small GTPase Rac1 is well known for regulating actin cytoskeleton reorganization in different type of cells, it appears to be also required for learning and the formation of memories in the brain. Abnormal regulation of this protein has been associated with cognitive disabilities, atypical synaptic plasticity and abnormal morphology of dendritic spines in certain neurodevelopmental disorders. Thus, modulation of Rac1 activity using novel inhibitors might be a strategy to reestablish cognitive function.
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Rac1 plays critical roles in modulating both the localization of neurotransmitter receptors and the architecture of excitatory synapses.
“Rac1, a master actin regulator, plays critical roles in modulating both the localization of neurotransmitter receptors and the architecture of excitatory synapses 3.”
From Autism-like social deficit generated by Dock4 deficiency is rescued by restoration of Rac1 activity and NMDA receptor function. (2021) · cites this paper as [3]
The Abstract describes Rac1 as an actin regulator important for dendritic spine morphogenesis, supporting its role in excitatory-synapse architecture. The section “Actin dynamics in neurons: link to intellectual disability” says glutamate receptors regulate Rac1, but does not say Rac1 controls the localization of neurotransmitter receptors; it describes Rac1 itself moving to the membrane after NMDA receptor activation. No page number is supplied for these passages. (LLM, conf=0.86)
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Guo, D., Peng, Y., Wang, L., Sun, X., Wang, X., Liang, C., Yang, X., Li, S., Xu, J., Ye, W.-C., et al. (2021) · Molecular Psychiatry · doi:10.1038/s41380-019-0472-7 · Cited by 102 · see citing works
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- Authors
- Tejada‐Simon, M. V.
- Affiliations
- Department of Pharmacological and Pharmaceutical Sciences University of Houston Houston Texas USA
- Venue
- Journal of Neurochemistry
- Publisher
- Wiley
- Published
- 2015-04-22
- Volume
- 133
- Issue
- 6
- Pages
- 767-779
- ISSN
- 0022-3042 (ISSN-L)
- 1471-4159
- OpenAlex
- W2027930171
- Cited by
- 76
- References
- 11
- Citations by year
- 2026: 6 · 2025: 4 · 2024: 10 · 2023: 11 · 2022: 5 · 2021: 8 · 2020: 5 · 2019: 5 · 2018: 9 · 2017: 8 · 2016: 4 · 2015: 1
- FWCI
- 0.71
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neurochemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- FRAXA Research Foundation
- Jerome LeJeune Foundation
- GEAR-UH grant program
- SGP-UH grant program
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- Rac1, actin cytoskeleton, dendritic spine morphogenesis, cognitive impairment, Rac1 inhibitor, neurodevelopmental disorders, synaptic plasticity, learning and memory, intellectual disability, small GTPases
- MeSH terms
- Actins, Animals, Mental Disorders, Brain, Cognition, Humans, rac1 GTP-Binding Protein, Neurogenesis
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