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Gabapentin Receptor α2δ-1 Is a Neuronal Thrombospondin Receptor Responsible for Excitatory CNS Synaptogenesis
Open accessAbstract
Synapses are asymmetric cellular adhesions that are critical for nervous system development and function, but the mechanisms that induce their formation are not well understood. We have previously identified thrombospondin as an astrocyte-secreted protein that promotes central nervous system (CNS) synaptogenesis. Here, we identify the neuronal thrombospondin receptor involved in CNS synapse formation as alpha2delta-1, the receptor for the anti-epileptic and analgesic drug gabapentin. We show that the VWF-A domain of alpha2delta-1 interacts with the epidermal growth factor-like repeats common to all thrombospondins. alpha2delta-1 overexpression increases synaptogenesis in vitro and in vivo and is required postsynaptically for thrombospondin- and astrocyte-induced synapse formation in vitro. Gabapentin antagonizes thrombospondin binding to alpha2delta-1 and powerfully inhibits excitatory synapse formation in vitro and in vivo. These findings identify alpha2delta-1 as a receptor involved in excitatory synapse formation and suggest that gabapentin may function therapeutically by blocking new synapse formation.
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“For example, astrocytes secrete thrombospondins, which bind their receptors ␣2␦1 on neurons to stimulate synapse formation (Christopherson et al., 2005;Eroglu et al., 2009).”
From An RNA-Sequencing Transcriptome and Splicing Database of Glia, Neurons, and Vascular Cells of the Cerebral Cortex (2014) · cites this paper as Eroglu et al., 2009
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“Beyond these PNN-associated compounds also proteins released by astrocytes influence synaptogenesis, for example thrombospondins and the gabapentin receptor55,73, Hevin and SPARC56, or Pentraxin 3 that promotes excitatory synapse formation by fostering the clustering of AMPA glutamate receptors74.”
From Elimination of the four extracellular matrix molecules tenascin-C, tenascin-R, brevican and neurocan alters the ratio of excitatory and inhibitory synapses (2019) · cites this paper as [73]
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Reactive astrocytes: cellular and molecular cues to biological function
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Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis
Christopherson, K. S., Ullian, E. M., Stokes, C. C. A., Mullowney, C. E., Hell, J. W., Agah, A., Lawler, J., Mosher, D. F., Bornstein, P., & Barres, B. A. (2005) · Cell · doi:10.1016/j.cell.2004.12.020 · Cited by 1,688
Self-citationControl of Synapse Number by Glia
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Self-citationThe Novel Anticonvulsant Drug, Gabapentin (Neurontin), Binds to the α2δ Subunit of a Calcium Channel
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Stargazin regulates synaptic targeting of AMPA receptors by two distinct mechanisms
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Self-citationWhittaker, C., & Hynes, R. (2002) · Molecular Biology of the Cell · doi:10.1091/mbc.e02-05-0259 · Cited by 788
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Self-citationVGLUTs define subsets of excitatory neurons and suggest novel roles for glutamate
Fremeau, R. T., Voglmaier, S., Seal, R. P., & Edwards, R. H. (2004) · Trends in Neurosciences · doi:10.1016/j.tins.2003.11.005 · Cited by 745
Unusual spectral energy distribution of a galaxy previously reported to be at redshift 6.68
Chen, H., Lanzetta, K. M., Pascarelle, S. M., & Yahata, N. (2000) · RePEc: Research Papers in Economics · Cited by 680
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“For example, astrocytes secrete thrombospondins, which bind their receptors 2 1 on neurons to stimulate synapse formation (Christopherson et al., 2005; Eroglu et al., 2009).”
Self-citationExtracellular matrix structure
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Metadata
- Authors
- Eroglu, Ç., Allen, N. J., Susman, M. W., O'Rourke, N. A., Park, C. Y., Özkan, E., Chakraborty, C., Mulinyawe, S. B., Annis, D. S., Huberman, A. D., Green, E. M., Lawler, J., Dolmetsch, R., Garcia, K. C., Smith, S. J., Luo, Z. D., Rosenthal, A., Mosher, D. F., & Barres, B. A.
- Affiliations
- Stanford Medicine (US)
- Howard Hughes Medical Institute (US)
- University of Wisconsin–Madison (US)
- Beth Israel Deaconess Medical Center (US)
- University of California, Irvine Medical Center (US)
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2009-10
- Volume
- 139
- Issue
- 2
- Pages
- 380-392
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC2791798
- OpenAlex
- W1988452935
- Cited by
- 893
- References
- 49
- Citations by year
- 2026: 30 · 2025: 47 · 2024: 62 · 2023: 57 · 2022: 52 · 2021: 59 · 2020: 68 · 2019: 41 · 2018: 54 · 2017: 53 · 2016: 50 · 2015: 41 · 2014: 54 · 2013: 66 · 2012: 56
- FWCI
- 21.76
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 1421 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Scholarworks@UNIST (Ulsan National Institute of Science and Technology) (submittedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL049081, HL49081)
- National Institute on Drug Abuse (R01DA015043, R37DA015043, DA15043)
- National Institute of Neurological Disorders and Stroke (NS-40135, R01NS040135)
- National Institute of Dental and Craniofacial Research (R21DE014545, DE14545)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- thrombospondin, synaptogenesis, excitatory synapses, astrocytes, epidermal growth factor-like repeats, synaptic adhesion, postsynaptic receptors, gabapentin, central nervous system development, synaptic plasticity
- MeSH terms
- Gabapentin, Amines, Animals, Cyclohexanecarboxylic Acids, gamma-Aminobutyric Acid, Neuronal Plasticity, Neurons, Synapses, Calcium Channels, Rats, Sprague-Dawley, CD36 Antigens, Calcium Channels, L-Type, Mice, Rats, Neurogenesis
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