Abstract
Spatial localization and clustering of membrane proteins is critical to neuronal development and synaptic plasticity. Recent studies have identified a family of proteins, the PDZ proteins, that contain modular PDZ domains and interact with synaptic ionotropic glutamate receptors1 and ion channels2. PDZ proteins are thought to have a role in defining the cellular distribution of the proteins that interact with them. Here we report a novel dendritic protein, Homer, that contains a single, PDZ-like domain and binds specifically to the carboxy terminus of phosphoinositide-linked metabotropic glutamate receptors. Homer is highly divergent from known PDZ proteins and seems to represent a novel family. The Homer gene is also distinct from members of the PDZ family in that its expression is regulated as an immediate early gene and is dynamically responsive to physiological synaptic activity, particularly during cortical development. This dynamic transcriptional control suggests that Homer mediates a novel cellular mechanism that regulates metabotropic glutamate signalling.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Kornau, H. C., Schenker, L. T., Kennedy, M. B. & Seeburg, P. H. Domain interaction between NMDA receptor subunits and the postsynaptic density protein PSD-95. Science 269, 1737–1740 (1995).
Kim, E., Niethammer, M., Rothschild, A., Jan, Y. N. & Sheng, M. Clustering of Shaker-type K+ channels by interaction with a family of membrane-associated guanylate kinases. Nature 378, 85–88 (1995).
Goelet, P., Castellucci, V., Schlacher, S. & Kandel, E. The long and the short of long-term memory—a molecular framework. Nature 322, 419–422 (1986).
Nguyen, P. V., Abel, T. & Kandel, E. R. Requirement of a critical period of transcription for induction of a late phase of LTP. Science 265, 1104–1107 (1994).
Nedivi, E., Hevroni, D., Naot, D., Israeli, D. & Citri, Y. Numerous candidate plasticity-related genes revealed by differential cDNA cloning. Nature 363, 713–722 (1993).
Qian, Z., Gilbert, M. E., Colicos, M. A., Kandel, E. R. & Kuhl, D. Tissue-plasminogen activator is induced as an immediate-early gene during seizure, kindling and long-term potentiation. Nature 361, 453–457 (1993).
Yamagata, K., Andreasson, K. I., Kaufmann, W. E., Barnes, C. A. & Worley, P. F. Expression of a mitogen-inducible cyclooxygenase in brain neurons: regulation by synaptic activity and glucocorticoids. Neuron 11, 371–386 (1993).
Yamagata, K. et al. Rheb, a growth factor and synaptic activity regulated gene, encodes a novel Ras-related protein. J. Biol. Chem. 269, 16333–16339 (1994).
Lyford, G. et al. Arc, a growth factor and activity-regulated gene encodes a novel cytoskeleton-associated protein that is enriched in neuronal dendrites. Neuron 14, 433–445 (1995).
Tsui, C. et al. Narp, a novel member of the pentraxin family, promotes neurite outgrowth and is dynamically regulated by neuronal activity. J. Neurosci. 16, 2463–2478 (1996).
Shaw, G. & Kamen, R. A conserved AU sequence from the 3′ untranslated region of GM-CSF mRNA mediates selective mRNA degradation. Cell 46, 659–667 (1986).
Doyle, D. A. et al. Crystal structures of a complexed and peptide-free membrane protein-binding domain—molecular basis of peptide recognition by PDZ. Cell 85, 1067–1076 (1996).
Nakanishi, S. Metabotropic glutamate receptors: synaptic transmission, modulation, and plasticity. Neuron 13, 1031–1037 (1994).
Pin, J. P. & Duvoisin, R. The metabotropic glutamate receptors: structure and functions. Neuropharmacology 34, 1–26 (1995).
Romano, C. et al. Distribution of metabotropic glutamate receptor mGluR5 immunoreactivity in rat brain. Comp. Neurol. 355, 455–469 (1995).
Martin, L. J., Blackstone, C. D., Huganir, R. L. & Price, D. L. Cellular localization of a metabotropic glutamate receptor in rat brain. Neuron 9, 259–270 (1992).
Worley, P. F. et al. Synaptic regulation of immediate early genes in brain. Cold Spring Harb. Symp. Quant. Biol. 55, 213–223 (1990).
Hyman, S. E., Cole, R. L., Konradi, C. & Kosofsky, B. E. Dopamine regulation of transcription factor-target interactions in rat striatum. Chem. Senses 20, 257–260 (1995).
Bhat, R. V. & Baraban, J. M. Activation of transcription factor genes in striatum by cocaine: role of both serotonin and dopamine systems. J. Pharmacol. Exp. Ther. 267, 496–505 (1993).
Pin, J. P., Joly, C., Heinemann, S. F. & Bockaert, J. Domains involved in the specificity of G protein activation in phospholipase C-coupled metabotropic glutamate receptors. EMBO J. 13, 342–348 (1994).
Joly, C. et al. Molecular, functional, and pharmacological characterization of the metabotropic glutamate receptor type 5 splice variants: comparison with mGluRl. J. Neurosci. 15, 3970–3981 (1995).
Flor, P. J. et al. The C-terminal domain of the mGluRl metabotropic glutamate receptor affects sensitivity to agonists. J. Neurochem. 67, 58–63 (1996).
Baude, A. et al. The metabotropic glutamate receptor (mGluRlα) is concentrated at perisynaptic membrane of neuronal subpopulations as detected by immunogold reaction. Neuron 11, 771–787 (1993).
Nusser, Z., Mulvihill, E., Streit, P. & Somogyi, P. Subsynaptic segregation of metabotropic and ionotropic glutamate receptors as revealed by immunogold localization. Neuroscience 61, 421–427 (1994).
Yee, W. & Worley, P. F. Rheb interacts with Raf-1 kinase and may function to integrate growth factor-and protein kinase A-dependent signals. Mol. Cell. Biol. 17, 921–933 (1997).
Chevray, P. M. & Nathans, D. Protein-interaction cloning in yeast—identification of mammalian proteins that react with the leucine zipper of Jun. Proc. Nat. Acad. Sci. USA 89, 5789–5792 (1992).
Dong, H. et al. GRIP: a synaptic PD2 domain-containing protein that interacts with AMPA receptors Nature 386, 279–284 (1997).
Worley, P. F. et al. Thresholds for synaptic activation of transcription factors in hippocampus: correlation with long-term enhancement. J. Neurosci. 13, 4776–4786 (1993).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Brakeman, P., Lanahan, A., O'Brien, R. et al. Homer: a protein that selectively binds metabotropic glutamate receptors. Nature 386, 284–288 (1997). https://doi.org/10.1038/386284a0
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/386284a0
This article is cited by
-
Extracellular vesicle encapsulated Homer1a as novel nanotherapeutics against intracerebral hemorrhage in a mouse model
Journal of Neuroinflammation (2024)
-
Hippocampal ensemble dynamics and memory performance are modulated by respiration during encoding
Nature Communications (2023)
-
Differentiated somatic gene expression is triggered in the dorsal hippocampus and the anterior retrosplenial cortex by hippocampal synaptic plasticity prompted by spatial content learning
Brain Structure and Function (2023)
-
Analysis of sleep deprivation-associated Homer1 gene and protein acting on synaptic plasticity by bioinformatics and animal experiments
Anesthesiology and Perioperative Science (2023)
-
Activity dependent dissociation of the Homer1 interactome
Scientific Reports (2022)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.