The Gabapentin Receptor α2δ-1 is the Neuronal Thrombospondin Receptor Responsible for Excitatory CNS Synaptogenesis
By Ç. Eroglu, N. J. Allen, Michael W Susman, N. O’Rourke, Chan Young Park, E. Özkan, C. Chakraborty, Sara B. Mulinyawe, D. Annis, A. Huberman and 9 more. Cell, 2009
888 citations recorded by the source corpus.
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 CNS synaptogenesis. Here we identify the neuronal thrombospondin receptor involved in CNS synapse formation as α2δ–1, the receptor for the anti-epileptic and analgesic drug gabapentin. We show that the VWF-A domain of α2δ–1 interacts with the epidermal growth factor-like repeats common to all thrombospondins. α2δ–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 α2δ–1 and powerfully inhibits excitatory synapse formation in vitro and in vivo. These findings identify α2δ–1 as a receptor involved in excitatory synapse formation and suggest that gabapentin may function therapeutically by blocking new synapse formation.
Subfields: Cellular and Molecular Neuroscience, Cognitive Neuroscience
View Paper: https://www.semanticscholar.org/paper/b49cb40737dd90fe1f17913ee159e3eb24ffb075
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Citations in the corpus
- Astrocytes: a central element in neurological diseases (2016, background): “by acting through the neuronal receptor α2δ-1 [57].”
- Glia and pain: Is chronic pain a gliopathy? (2013, background): “may inhibit neuropathic pain via modulating synaptogenesis [58].”
- Neuronal voltage-gated calcium channels: structure, function, and dysfunction. (2014, positive): “Recent evidence indicates that Cava2d subunits act as thrombospondin receptors and it is possible that interactions with thrombospondin are involved in the aforementioned modulation of synaptic release (Eroglu et al., 2009).”
- The thrombospondins. (2011, background): “TSP-induced synapses in culture are ultrastructurally normal and presynaptically active, but lack postsynaptic activity (Christopherson et al. 2005; Eroglu et al. 2009).”
- Astrocytes Control Synapse Formation, Function, and Elimination (2015, positive): “…Structural synapse formation Thrombospondin Positive Induces glutamatergic synapse formation; secreted by astrocytes Christopherson et al. 2005; Eroglu et al. 2009; Xu et al. 2009a; Garcia et al. 2010; Hughes et al. Thrombospondin Positive and negative Increases synaptic glycine receptors;…”
- Astrocytes and disease: a neurodevelopmental perspective. (2012, background): “The Barres laboratory (Christopherson et al. 2005; Eroglu et al. 2009) identified the proteins involved as TSPs, a group of matricellular proteins that are expressed in astrocytes of the developing but not mature brain, and TSP1/2deficient mice were shown to have reduced numbers of synapses in vivo.”
- An RNA-Sequencing Transcriptome and Splicing Database of Glia, Neurons, and Vascular Cells of the Cerebral Cortex (2014, positive): “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).”
- G protein inhibition of CaV2 calcium channels (2010, background): “α 2 δ-1 and α 2 δ-2 subunits, and thrombospondin was recently identified as an endogenous α 2 δ ligand.(11,14) The Ca V β subunit has received considerable attention because of its prominent effects on channel trafficking and gating and particularly since the crystal structures of several subtypes w”
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- The Physiology, Pathology, and Pharmacology of Voltage-Gated Calcium Channels and Their Future Therapeutic Potential (2015, background): “Thrombospondins are secreted extracellular matrix proteins that promote synaptogenesis via binding to a postsynaptic receptor, which was identified to be a2d-1 (Eroglu et al., 2009).”