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SUMOylation regulates kainate-receptor-mediated synaptic transmission


The small ubiquitin-like modifier protein (SUMO) regulates transcriptional activity and the translocation of proteins across the nuclear membrane1. The identification of SUMO substrates outside the nucleus is progressing2 but little is yet known about the wider cellular role of protein SUMOylation. Here we report that in rat hippocampal neurons multiple SUMOylation targets are present at synapses and we show that the kainate receptor subunit GluR6 is a SUMO substrate. SUMOylation of GluR6 regulates endocytosis of the kainate receptor and modifies synaptic transmission. GluR6 exhibits low levels of SUMOylation under resting conditions and is rapidly SUMOylated in response to a kainate but not an N-methyl-D-aspartate (NMDA) treatment. Reducing GluR6 SUMOylation using the SUMO-specific isopeptidase SENP-1 prevents kainate-evoked endocytosis of the kainate receptor. Furthermore, a mutated non-SUMOylatable form of GluR6 is not endocytosed in response to kainate in COS-7 cells. Consistent with this, electrophysiological recordings in hippocampal slices demonstrate that kainate-receptor-mediated excitatory postsynaptic currents are decreased by SUMOylation and enhanced by deSUMOylation. These data reveal a previously unsuspected role for SUMO in the regulation of synaptic function.

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Figure 1: SUMOylation of GluR6 in brain and cultured hippocampal neurons.
Figure 2: GluR6a is SUMOylated after direct stimulation with kainate in cultured hippocampal neurons.
Figure 3: DeSUMOylation blocks kainate-induced GluR6 endocytosis.
Figure 4: Synaptic KARs are regulated by SUMOylation.


  1. Seeler, J. S. & Dejean, A. Nuclear and unclear functions of SUMO. Nature Rev. Mol. Cell Biol. 4, 690– 699 (2003)

    CAS  Article  Google Scholar 

  2. Wilson, V. G. & Rosas-Acosta, G. Wrestling with SUMO in a new arena. Sci. STKE 2005, pe32 (2005)

    PubMed  Google Scholar 

  3. Lerma, J. Roles and rules of kainate receptors in synaptic transmission. Nature Rev. Neurosci. 4, 481– 495 (2003)

    CAS  Article  Google Scholar 

  4. Jaskolski, F., Coussen, F. & Mulle, C. Subcellular localization and trafficking of kainate receptors. Trends Pharmacol. Sci. 26, 20– 26 (2005)

    CAS  Article  Google Scholar 

  5. Hilgarth, R. S. et al. Regulation and function of SUMO modification. J. Biol. Chem. 279, 53899– 53902 (2004)

    CAS  Article  Google Scholar 

  6. Johnson, E. S. Protein modification by SUMO. Annu. Rev. Biochem. 73, 355– 382 (2004)

    CAS  Article  Google Scholar 

  7. Suzuki, T. et al. A new 30-kDa ubiquitin-related SUMO-1 hydrolase from bovine brain. J. Biol. Chem. 274, 31131– 31134 (1999)

    CAS  Article  Google Scholar 

  8. Hay, R. T. SUMO: a history of modification. Mol. Cell 18, 1– 12 (2005)

    CAS  Article  Google Scholar 

  9. Martin, S. & Henley, J. M. Activity-dependent endocytic sorting of kainate receptors to recycling or degradation pathways. EMBO J. 23, 4749– 4759 (2004)

    CAS  Article  Google Scholar 

  10. Gong, L., Millas, S., Maul, G. G. & Yeh, E. T. Differential regulation of sentrinized proteins by a novel sentrin-specific protease. J. Biol. Chem. 275, 3355– 3359 (2000)

    CAS  Article  Google Scholar 

  11. Rajan, S., Plant, L. D., Rabin, M. L., Butler, M. H. & Goldstein, S. A. Sumoylation silences the plasma membrane leak K+ channel K2P1. Cell 121, 37– 47 (2005)

    CAS  Article  Google Scholar 

  12. Uchimura, Y., Nakao, M. & Saitoh, H. Generation of SUMO-1 modified proteins in E. coli: towards understanding the biochemistry/structural biology of the SUMO-1 pathway. FEBS Lett. 564, 85– 90 (2004)

    CAS  Article  Google Scholar 

  13. Vignes, M. & Collingridge, G. L. The synaptic activation of kainate receptors. Nature 388, 179– 182 (1997)

    ADS  CAS  Article  Google Scholar 

  14. Castillo, P. E., Malenka, R. C. & Nicoll, R. A. Kainate receptors mediate a slow postsynaptic current in hippocampal CA3 neurons. Nature 388, 182– 188 (1997)

    ADS  CAS  Article  Google Scholar 

  15. Mulle, C. et al. Altered synaptic physiology and reduced susceptibility to kainate- induced seizures in GluR6-deficient mice. Nature 392, 601– 605 (1998)

    ADS  CAS  Article  Google Scholar 

  16. Luscher, C. et al. Role of AMPA receptor cycling in synaptic transmission and plasticity. Neuron 24, 649– 658 (1999)

    CAS  Article  Google Scholar 

  17. Borgdorff, A. J. & Choquet, D. Regulation of AMPA receptor lateral movements. Nature 417, 649– 653 (2002)

    ADS  CAS  Article  Google Scholar 

  18. Comerford, K. M. et al. Small ubiquitin-related modifier-1 modification mediates resolution of CREB-dependent responses to hypoxia. Proc. Natl Acad. Sci. USA 100, 986– 991 (2003)

    ADS  CAS  Article  Google Scholar 

  19. Zhang, J. et al. c-fos regulates neuronal excitability and survival. Nature Genet. 30, 416– 420 (2002)

    CAS  Article  Google Scholar 

  20. Hirbec, H. et al. Rapid and differential regulation of AMPA and kainate receptors at hippocampal mossy fibre synapses by PICK1 and GRIP. Neuron 37, 625– 638 (2003)

    CAS  Article  Google Scholar 

  21. Coussen, F. et al. Co-assembly of two GluR6 kainate receptor splice variants within a functional protein complex. Neuron 47, 555– 566 (2005)

    CAS  Article  Google Scholar 

  22. Nishimune, A. et al. NSF binding to GluR2 regulates synaptic transmission. Neuron 21, 87– 97 (1998)

    CAS  Article  Google Scholar 

  23. Kim, J. et al. Sindbis vector SINrep(nsP2S726): a tool for rapid heterologous expression with attenuated cytotoxicity in neurons. J. Neurosci. Methods 133, 81– 90 (2004)

    CAS  Article  Google Scholar 

  24. Hirbec, H., Martin, S. & Henley, J. M. Syntenin is involved in the developmental regulation of neuronal membrane architecture. Mol. Cell. Neurosci. 28, 737– 746 (2005)

    CAS  Article  Google Scholar 

  25. Fleck, M. W., Cornell, E. & Mah, S. J. Amino-acid residues involved in glutamate receptor 6 kainate receptor gating and desensitization. J. Neurosci. 23, 1219– 1227 (2003)

    CAS  Article  Google Scholar 

  26. Mah, S. J., Cornell, E., Mitchell, N. A. & Fleck, M. W. Glutamate receptor trafficking: endoplasmic reticulum quality control involves ligand binding and receptor function. J. Neurosci. 25, 2215– 2225 (2005)

    CAS  Article  Google Scholar 

  27. Lee, H. K., Kameyama, K., Huganir, R. L. & Bear, M. F. NMDA induces long-term synaptic depression and dephosphorylation of the GluR1 subunit of AMPA receptors in hippocampus. Neuron 21, 1151– 1162 (1998)

    CAS  Article  Google Scholar 

  28. Daw, M. I. et al. PDZ proteins interacting with C-terminal GluR2/3 are involved in a PKC- dependent regulation of AMPA receptors at hippocampal synapses. Neuron 28, 873– 886 (2000)

    CAS  Article  Google Scholar 

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We acknowledge the Wellcome Trust (J.M.H.), the MRC (J.R.M. and J.M.H.) and the EU (J.M.H. from a GRIPPANT contract) for financial support. We thank G. Hodgkinson for validation electrophysiology experiments on recombinant GluR6 in HEK cells, and S. Correa for some preliminary immuno cytochemistry experiments. We also thank M. Fleck for anti-GluR6 antibody, S. Goldstein for the SENP-1 constructs, C. Mulle for the pcDNA3-myc-GluR6 and H. Saitoh for the bacterial SUMOylation system. We are grateful to M. Ashby, G. Banting, Z. Bashir, T. Bouschet, G. Collingridge, J. Hanley, J. Isaac, F. Jaskolski, A. Randall and D. Stephens for commenting on the manuscript.

Author Contributions S.M. and A. N. are co-first authors; J.R.M. and J.M.H. are co-last authors. S.M. performed surface expression, biochemistry and cell imaging assays in cell culture. A.N. made the original observation that GluR6a is a SUMOylation substrate, performed biochemistry on brain extracts and performed all molecular biological experiments. J.R.M. performed the electrophysiology experiments and co-wrote the manuscript. J.M.H. provided team leadership, project management and wrote the manuscript. All authors contributed to hypothesis development, experimental design and data interpretation.

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Correspondence to Jeremy M. Henley.

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Martin, S., Nishimune, A., Mellor, J. et al. SUMOylation regulates kainate-receptor-mediated synaptic transmission. Nature 447, 321–325 (2007).

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