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Stargazin regulates synaptic targeting of AMPA receptors by two distinct mechanisms

Nature volume 408, pages 936–943 (2000)Cite this article

Abstract

Stargazer, an ataxic and epileptic mutant mouse, lacks functional AMPA (α-amino-3-hydroxyl-5-methyl-4-isoxazolepropionate) receptors on cerebellar granule cells. Stargazin, the mutated protein, interacts with both AMPA receptor subunits and synaptic PDZ proteins, such as PSD-95. The interaction of stargazin with AMPA receptor subunits is essential for delivering functional receptors to the surface membrane of granule cells, whereas its binding with PSD-95 and related PDZ proteins through a carboxy-terminal PDZ-binding domain is required for targeting the AMPA receptor to synapses. Expression of a mutant stargazin lacking the PDZ-binding domain in hippocampal pyramidal cells disrupts synaptic AMPA receptors, indicating that stargazin-like mechanisms for targeting AMPA receptors may be widespread in the central nervous system.

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Figure 1: Functional AMPARs are absent at stg/stg granule cell synapses in culture.
Figure 2: AMPAR immunogold labelling of cerebellar mossy fibre-granule cell synapses.
Figure 3: Ca2+ currents recorded from +/stg and stg/stg granule cells.
Figure 4: Interactions between Stargazin, GluR and PDZ proteins.
Figure 5: Surface AMPARs are absent in stg/stg granule cells.
Figure 6: Stargazin rescues AMPAR responses in stg/stg granule cells.
Figure 7: StargazinΔC downregulates hippocampal excitatory synapses.

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References

  1. Luscher, C., Nicoll, R. A., Malenka, R. C. & Muller, D. Synaptic plasticity and dynamic modulation of the postsynaptic membrane. Nature Neurosci. 3, 545–550 (2000).

    Article  CAS  Google Scholar 

  2. Malenka, R. C. & Nicoll, R. A. Long-term potentiation—a decade of progress? Science 285, 1870–1874 (1999).

    Article  CAS  Google Scholar 

  3. Malinow, R., Mainen, Z. F. & Hayashi, Y. LTP mechanisms: from silence to four-lane traffic. Curr. Opin. Neurobiol. 10, 352–357.

  4. Liu, S. Q. & Cull-Candy, S. G. Synaptic activity at calcium-permeable AMPA receptors induces a switch in receptor subtype. Nature 405, 454–458 (2000).

    Article  ADS  CAS  Google Scholar 

  5. Luthi, A. et al. Hippocampal LTD expression involves a pool of AMPARs regulated by the NSF–GluR2 interaction. Neuron 24, 389–399 (1999).

    Article  CAS  Google Scholar 

  6. Man, Y. H. et al. Regulation of AMPA receptor-mediated synaptic transmission by clathrin-dependent receptor internalization. Neuron 25, 649–662 (2000).

    Article  CAS  Google Scholar 

  7. Song, I. et al. Interaction of the N-ethylmaleimide-sensitive factor with AMPA receptors. Neuron 21, 393–400 (1998).

    Article  CAS  Google Scholar 

  8. P. Osten, S. et al. The AMPA Receptor GluR2 C terminus can mediate a reversible, ATP-dependent interaction with NSF and SNAPs. Neuron 21, 99–110 (1998).

    Article  Google Scholar 

  9. Chen, L., Bao, S., Qiao, X. & Thompson, R. F. Impaired cerebellar synapse maturation in waggler, a mutant mouse with a disrupted neuronal calcium channel gamma subunit. Proc. Natl Acad. Sci. USA 96, 12132–12137 (1999).

    Article  ADS  CAS  Google Scholar 

  10. Hashimoto, K. et al. Impairment of AMPA receptor function in cerebellar granule cells of ataxic mutant mouse stargazer. J. Neurosci. 19, 6027–6036 (1999).

    Article  CAS  Google Scholar 

  11. Letts, V. A. et al. The mouse stargazer gene encodes a neuronal Ca2+-channel gamma subunit. Nature Genet. 19, 340–347 (1998).

    Article  CAS  Google Scholar 

  12. Burgess, D. L., Davis, C. F., Gefrides, L. A. & Noebels, J. L. Identification of three novel Ca2+ channel gamma subunit genes reveals molecular diversification by tandem and chromosome duplication. Genome Res. 9, 1204–1213 (1999).

    Article  CAS  Google Scholar 

  13. Klugbauer, N. et al. A family of gamma-like calcium channel subunits. FEBS Lett. 470, 189–197 (2000).

    Article  CAS  Google Scholar 

  14. Randall, A. & Tsien, R. W. Pharmacological dissection of multiple types of Ca2+ channel currents in rat cerebellar granule neurons. J. Neurosci. 15, 2995–3012 (1995).

    Article  CAS  Google Scholar 

  15. Hsueh, Y. P. et al. Direct interaction of CASK/LIN-2 and syndecan heparan sulfate proteoglycan and their overlapping distribution in neuronal synapses. J. Cell Biol. 142, 139–151 (1998).

    Article  CAS  Google Scholar 

  16. Torres, R. et al. PDZ proteins bind, cluster, and synaptically colocalize with Eph receptors and their ephrin ligands. Neuron 21, 1453–1463 (1998).

    Article  CAS  Google Scholar 

  17. 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).

    Article  ADS  CAS  Google Scholar 

  18. Monyer, H., Burnashev, N., Laurie, D. J., Sakmann, B. & Seeburg, P. H. Developmental and regional expression in the rat brain and functional properties of four NMDA receptors. Neuron 12, 529–540 (1994).

    Article  CAS  Google Scholar 

  19. Sheng, M. & Pak, D. T. Glutamate receptor anchoring proteins and the molecular organization of excitatory synapses. Ann. N. Y. Acad. Sci. 868, 483–493 (1999).

    Article  ADS  CAS  Google Scholar 

  20. Garner, C. C., Nash, J. & Huganir, R. L. PDZ domains in synapse assembly and signalling. Trends Cell Biol. 10, 274–280 (2000).

    Article  CAS  Google Scholar 

  21. Braithwaite, S. P., Meyer, G. & Henley, J. M. Interactions between AMPA receptors and intracellular proteins. Neuropharmacology. 39, 919–930 (2000).

    Article  CAS  Google Scholar 

  22. Osten, P. et al. Mutagenesis reveals a role for ABP/GRIP binding to GluR2 in synaptic surface accumulation of the AMPA receptor. Neuron 27, 313–325 (2000).

    Article  CAS  Google Scholar 

  23. Bao, S., Chen, L., Qiao, X., Knusel, B. & Thompson, R. F. Impaired eye-blink conditioning in waggler, a mutant mouse with cerebellar BDNF deficiency. Learn. Mem. 5, 355–364 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Wenthold, R. J., Yokotani, N., Doi, K. & Wada, K. Immunochemical characterization of the non-NMDA glutamate receptor using subunit-specific antibodies. Evidence for a hetero-oligomeric structure in rat brain. J. Biol. Chem. 267, 501–507 (1992).

    CAS  PubMed  Google Scholar 

  25. Petralia, R. S. & Wenthold, R. J. Light and electron immunocytochemical localization of AMPA-selective glutamate receptors in the rat brain. J. Comp. Neurol. 318, 329–354 (1992).

    Article  CAS  Google Scholar 

  26. Petralia, R. S., Yokotani, N. & Wenthold, R. J. Light and electron microscope distribution of the NMDA receptor subunit NMDAR1 in the rat nervous system using a selective anti-peptide antibody. J. Neurosci. 14, 667–696 (1994).

    Article  CAS  Google Scholar 

  27. Luo, J., Wang, Y., Yasuda, R. P., Dunah, A. W. & Wolfe, B. B. The majority of N-methyl-d-aspartate receptor complexes in adult rat cerebral cortex contain at least three different subunits (NR1/NR2A/NR2B). Mol. Pharmacol. 51, 79–86 (1997).

    Article  CAS  Google Scholar 

  28. El-Husseini, A. E. et al. Dual palmitoylation of PSD-95 mediates its vesiculotubular sorting, postsynaptic targeting, and ion channel clustering. J. Cell Biol. 148, 159–172 (2000).

    Article  CAS  Google Scholar 

  29. Lester, R. A. J., Quarum, M. L., Parker, J. D., Weber, E. & Jahr, C. E. Interaction of 6-cyano-7-nitroquinoxaline-2, 3-dione with the N-methyl-D-aspartate receptor-associated glycine binding site. Mol. Pharmacol. 35, 565–570 (1989).

    CAS  PubMed  Google Scholar 

  30. Jo, K., Derin, R., Li, M. & Bredt, D. S. Characterization of MALS/Velis-1,-2, and-3: a family of mammalian LIN-7 homologs enriched at brain synapses in association with the postsynaptic density-95/NMDA receptor postsynaptic complex. J. Neurosci. 19, 4189–4199 (1999).

    Article  CAS  Google Scholar 

  31. Lester, R. A. J. & Jahr, C. E. NMDA channel behavior depends on agonist affinity. J. Neurosci. 12, 635–643 (1992).

    Article  CAS  Google Scholar 

  32. Wang, Y. -X., Wenthold, R. J., Ottersen, O. P. & Petralia, R. S. Endbulb synapses in the anteroventral cochlear nucleus express a specific subset of AMPA-type glutamate receptor subunits. J. Neurosci. 18, 1148–1160 (1998).

    Article  CAS  Google Scholar 

  33. Petralia, R. S., Zhao, H. M., Wang, Y. X. & Wenthold, R. J. Variations in the tangential distribution of postsynaptic glutamate receptors in Purkinje cell parallel and climbing fibre synapses during development. Neuropharmacology 37, 1321–1334 (1998).

    Article  CAS  Google Scholar 

  34. Petralia, R. S. et al. Selective acquisition of AMPA receptors over postnatal development suggests a molecular basis for silent synapses. Nature Neurosci. 2, 31–36 (1999).

    Article  CAS  Google Scholar 

  35. Zhao, H. M., Wenthold, R. J. & Petralia, R. S. Glutamate receptor targeting to synaptic populations on Purkinje cells is developmentally regulated. J. Neurosci. 18, 5517–5528 (1998).

    Article  CAS  Google Scholar 

  36. Matsubara, A., Laake, J. H., Davanger, S., Usami, S. & Ottersen, O. P. Organization of AMPA receptor subunits at a glutamate synapse: a quantitative immunogold analysis of hair cell synapses in the rat organ of Corti. J. Neuroscience 16, 4457–4467 (1996).

    Article  CAS  Google Scholar 

  37. Palay, S. L. & Chan-Palay, V. Cerebellar Cortex. Cytology and Organization (Springer, New York, 1974).

    Book  Google Scholar 

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Acknowledgements

We thank R. F. Thompson and X. Qiao for providing the initial stargazer breeding pairs; K. P. Campbell for providing a stargazin antibody used in preliminary experiments; B. B. Wolfe for providing the NR1 monoclonal antibody used in the electron microscopy study; S. Tomita for subcloning Stargazin-3; E. Schnell for assisting in hippocampal culture transfection; Q. Zhou for assisting in confocal microscopy; and Y.-X. Wang for assisting in immunogold labelling. We also thank M. Frerking, L. Jan and D. Julius for their comments on the manuscript. D.S.B is supported by grants from NIH and HHMI. R.A.N. is supported by grants from the NIH and Bristol-Myers Squibb. D.S.B. is an established investigator of the American Heart Association, D.M.C. is a postdoctoral fellow of the HHMI. R.A.N. is a member of the Keck Center for Integrative Neuroscience and the Silvio Conte Center for Neuroscience Research.

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  1. Lu Chen and Dane M. Chetkovich: These authors contributed equally to this work

Authors and Affiliations

  1. Cellular and Molecular Pharmacology,,

    Lu Chen & Roger A. Nicoll

  2. Departments of Physiology,

    Dane M. Chetkovich, Neal T. Sweeney, Yoshimi Kawasaki, David S. Bredt & Roger A. Nicoll

  3. Departments of Neurology, University of California, San Francisco, 94143, California, USA

    Dane M. Chetkovich

  4. Laboratory of Neurochemistry, NIDCD, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Ronald S. Petralia & Robert J. Wenthold

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Chen, L., Chetkovich, D., Petralia, R. et al. Stargazin regulates synaptic targeting of AMPA receptors by two distinct mechanisms. Nature 408, 936–943 (2000). https://doi.org/10.1038/35050030

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