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A neuronal role for SNAP-23 in postsynaptic glutamate receptor trafficking

Nature Neuroscience volume 13, pages 338–343 (2010)Cite this article

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Abstract

Regulated exocytosis is essential for many biological processes and many components of the protein trafficking machinery are ubiquitous. However, there are also exceptions, such as SNAP-25, a neuron-specific SNARE protein that is essential for synaptic vesicle release from presynaptic nerve terminals. In contrast, SNAP-23 is a ubiquitously expressed SNAP-25 homolog that is critical for regulated exocytosis in non-neuronal cells. However, the role of SNAP-23 in neurons has not been elucidated. We found that SNAP-23 was enriched in dendritic spines and colocalized with constituents of the postsynaptic density, whereas SNAP-25 was restricted to axons. In addition, loss of SNAP-23 using genetically altered mice or shRNA targeted to SNAP-23 led to a marked decrease in NMDA receptor surface expression and NMDA receptor currents, whereas loss of SNAP-25 did not. SNAP-23 is therefore important for the functional regulation of postsynaptic glutamate receptors.

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Figure 1: SNAP-25 and SNAP-23 are differentially expressed in neurons.
Figure 2: Endogenous SNAP-23 is enriched at excitatory synapses on dendritic spines.
Figure 3: NMDA receptor surface expression is reduced in SNAP-23 heterozygous mice.
Figure 4: SNAP-23, but not SNAP-25, regulates surface expression of NMDA receptors.
Figure 5: SNAP-23 regulates the recycling of the NMDA receptor subunit NR2B.
Figure 6: Knockdown of SNAP-23 causes a reduction in NMDA-evoked currents and NMDA EPSCs in CA1 pyramidal neurons.

References

  1. Mayer, A. Membrane fusion in eukaryotic cells. Annu. Rev. Cell Dev. Biol. 18, 289–314 (2002).

    Article  CAS  Google Scholar 

  2. Jahn, R. & Sudhof, T.C. Membrane fusion and exocytosis. Annu. Rev. Biochem. 68, 863–911 (1999).

    Article  CAS  Google Scholar 

  3. Jahn, R. & Scheller, R.H. SNAREs - engines for membrane fusion. Nat. Rev. Mol. Cell Biol. 7, 631–643 (2006).

    Article  CAS  Google Scholar 

  4. Lin, R.C. & Scheller, R.H. Mechanisms of synaptic vesicle exocytosis. Annu. Rev. Cell Dev. Biol. 16, 19–49 (2000).

    Article  CAS  Google Scholar 

  5. Duc, C. & Catsicas, S. Ultrastructural localization of SNAP-25 within the rat spinal cord and peripheral nervous system. J. Comp. Neurol. 356, 152–163 (1995).

    Article  CAS  Google Scholar 

  6. Oyler, G.A. et al. The identification of a novel synaptosomal-associated protein, SNAP-25, differentially expressed by neuronal subpopulations. J. Cell Biol. 109, 3039–3052 (1989).

    Article  CAS  Google Scholar 

  7. Tao-Cheng, J.H., Du, J. & McBain, C.J. Snap-25 is polarized to axons and abundant along the axolemma: an immunogold study of intact neurons. J. Neurocytol. 29, 67–77 (2000).

    Article  CAS  Google Scholar 

  8. Washbourne, P. et al. Genetic ablation of the t-SNARE SNAP-25 distinguishes mechanisms of neuroexocytosis. Nat. Neurosci. 5, 19–26 (2002).

    Article  CAS  Google Scholar 

  9. Ravichandran, V., Chawla, A. & Roche, P.A. Identification of a novel syntaxin- and synaptobrevin/VAMP-binding protein, SNAP-23, expressed in non-neuronal tissues. J. Biol. Chem. 271, 13300–13303 (1996).

    Article  CAS  Google Scholar 

  10. Chen, D., Bernstein, A.M., Lemons, P.P. & Whiteheart, S.W. Molecular mechanisms of platelet exocytosis: role of SNAP-23 and syntaxin 2 in dense core granule release. Blood 95, 921–929 (2000).

    CAS  PubMed  Google Scholar 

  11. Foster, L.J., Yaworsky, K., Trimble, W.S. & Klip, A. SNAP23 promotes insulin-dependent glucose uptake in 3T3–L1 adipocytes: possible interaction with cytoskeleton. Am. J. Physiol. 276, 1108–1114 (1999).

    Article  Google Scholar 

  12. Guo, Z., Turner, C. & Castle, D. Relocation of the t-SNARE SNAP-23 from lamellipodia-like cell surface projections regulates compound exocytosis in mast cells. Cell 94, 537–548 (1998).

    Article  CAS  Google Scholar 

  13. Vaidyanathan, V.V., Puri, N. & Roche, P.A. The last exon of SNAP-23 regulates granule exocytosis from mast cells. J. Biol. Chem. 276, 25101–25106 (2001).

    Article  CAS  Google Scholar 

  14. Bragina, L. et al. Heterogeneity of glutamatergic and GABAergic release machinery in cerebral cortex. Neuroscience 146, 1829–1840 (2007).

    Article  CAS  Google Scholar 

  15. Chen, D., Minger, S.L., Honer, W.G. & Whiteheart, S.W. Organization of the secretory machinery in the rodent brain: distribution of the t-SNAREs, SNAP-25 and SNAP-23. Brain Res. 831, 11–24 (1999).

    Article  CAS  Google Scholar 

  16. Verderio, C. et al. SNAP-25 modulation of calcium dynamics underlies differences in GABAergic and glutamatergic responsiveness to depolarization. Neuron 41, 599–610 (2004).

    Article  CAS  Google Scholar 

  17. Sadoul, K. et al. SNAP-23 is not cleaved by botulinum neurotoxin E and can replace SNAP-25 in the process of insulin secretion. J. Biol. Chem. 272, 33023–33027 (1997).

    Article  CAS  Google Scholar 

  18. Lau, C.G. & Zukin, R.S. NMDA receptor trafficking in synaptic plasticity and neuropsychiatric disorders. Nat. Rev. Neurosci. 8, 413–426 (2007).

    Article  CAS  Google Scholar 

  19. Wenthold, R.J., Prybylowski, K., Standley, S., Sans, N. & Petralia, R.S. Trafficking of NMDA receptors. Annu. Rev. Pharmacol. Toxicol. 43, 335–358 (2003).

    Article  CAS  Google Scholar 

  20. Groc, L. & Choquet, D. AMPA and NMDA glutamate receptor trafficking: multiple roads for reaching and leaving the synapse. Cell Tissue Res. 326, 423–438 (2006).

    Article  CAS  Google Scholar 

  21. Roche, K.W. et al. Molecular determinants of NMDA receptor internalization. Nat. Neurosci. 4, 794–802 (2001).

    Article  CAS  Google Scholar 

  22. Lavezzari, G., McCallum, J., Dewey, C.M. & Roche, K.W. Subunit-specific regulation of NMDA receptor endocytosis. J. Neurosci. 24, 6383–6391 (2004).

    Article  CAS  Google Scholar 

  23. Sans, N. et al. NMDA receptor trafficking through an interaction between PDZ proteins and the exocyst complex. Nat. Cell Biol. 5, 520–530 (2003).

    Article  CAS  Google Scholar 

  24. Washbourne, P., Liu, X.B., Jones, E.G. & McAllister, A.K. Cycling of NMDA receptors during trafficking in neurons before synapse formation. J. Neurosci. 24, 8253–8264 (2004).

    Article  CAS  Google Scholar 

  25. Tovar, K.R. & Westbrook, G.L. Mobile NMDA receptors at hippocampal synapses. Neuron 34, 255–264 (2002).

    Article  CAS  Google Scholar 

  26. Oyler, G.A., Polli, J.W., Wilson, M.C. & Billingsley, M.L. Developmental expression of the 25-kDa synaptosomal-associated protein (SNAP-25) in rat brain. Proc. Natl. Acad. Sci. USA 88, 5247–5251 (1991).

    Article  CAS  Google Scholar 

  27. Vaidyanathan, V.V. & Roche, P.A. Structure and chromosomal localization of the mouse Snap23 gene. Gene 247, 181–189 (2000).

    Article  CAS  Google Scholar 

  28. Cahill, A.L., Herring, B.E. & Fox, A.P. Stable silencing of SNAP-25 in PC12 cells by RNA interference. BMC Neurosci. 7, 9 (2006).

    Article  Google Scholar 

  29. Scott, D.B., Michailidis, I., Mu, Y., Logothetis, D. & Ehlers, M.D. Endocytosis and degradative sorting of NMDA receptors by conserved membrane-proximal signals. J. Neurosci. 24, 7096–7109 (2004).

    Article  CAS  Google Scholar 

  30. Sutton, R.B., Fasshauer, D., Jahn, R. & Brunger, A.T. Crystal structure of a SNARE complex involved in synaptic exocytosis at 2.4 angstrom resolution. Nature 395, 347–353 (1998).

    Article  CAS  Google Scholar 

  31. Leung, S.M., Chen, D., DasGupta, B.R., Whiteheart, S.W. & Apodaca, G. SNAP-23 requirement for transferrin recycling in Streptolysin-O-permeabilized Madin-Darby canine kidney cells. J. Biol. Chem. 273, 17732–17741 (1998).

    Article  CAS  Google Scholar 

  32. Lledo, P.M., Zhang, X., Sudhof, T.C., Malenka, R.C. & Nicoll, R.A. Postsynaptic membrane fusion and long-term potentiation. Science 279, 399–403 (1998).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  36. Lan, J.Y. et al. Protein kinase C modulates NMDA receptor trafficking and gating. Nat. Neurosci. 4, 382–390 (2001).

    Article  CAS  Google Scholar 

  37. Lan, J.Y. et al. Activation of metabotropic glutamate receptor 1 accelerates NMDA receptor trafficking. J. Neurosci. 21, 6058–6068 (2001).

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  39. Selak, S. et al. A role for SNAP25 in internalization of kainate receptors and synaptic plasticity. Neuron 63, 357–371 (2009).

    Article  CAS  Google Scholar 

  40. Hayashi, T. et al. Synaptic vesicle membrane fusion complex: action of clostridial neurotoxins on assembly. EMBO J. 13, 5051–5061 (1994).

    Article  CAS  Google Scholar 

  41. Petralia, R.S., Sans, N., Wang, Y.X. & Wenthold, R.J. Ontogeny of postsynaptic density proteins at glutamatergic synapses. Mol. Cell. Neurosci. 29, 436–452 (2005).

    Article  CAS  Google Scholar 

  42. Petralia, R.S., Wang, Y.X. & Wenthold, R.J. Internalization at glutamatergic synapses during development. Eur. J. Neurosci. 18, 3207–3217 (2003).

    Article  Google Scholar 

  43. Petralia, R.S. & Wenthold, R.J. Immunocytochemistry of NMDA receptors. Methods Mol. Biol. 128, 73–92 (1999).

    CAS  PubMed  Google Scholar 

  44. Yi, Z. et al. The role of the PDZ protein GIPC in regulating NMDA receptor trafficking. J. Neurosci. 27, 11663–11675 (2007).

    Article  CAS  Google Scholar 

  45. Carlin, R.K., Grab, D.J., Cohen, R.S. & Siekevitz, P. Isolation and characterization of postsynaptic densities from various brain regions: enrichment of different types of postsynaptic densities. J. Cell Biol. 86, 831–845 (1980).

    Article  CAS  Google Scholar 

  46. Schlüter, O.M., Xu, W. & Malenka, R.C. Alternative N-terminal domains of PSD-95 and SAP97 govern activity-dependent regulation of synaptic AMPA receptor function. Neuron 51, 99–111 (2006).

    Article  Google Scholar 

  47. Suh, Y.H. et al. Corequirement of PICK1 binding and PKC phosphorylation for stable surface expression of the metabotropic glutamate receptor mGluR7. Neuron 58, 736–748 (2008).

    Article  CAS  Google Scholar 

  48. Terashima, A. et al. An essential role for PICK1 in NMDA receptor-dependent bidirectional synaptic plasticity. Neuron 57, 872–882 (2008).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Y.-X. Wang for help with immunogold labeling, J.D. Badger II for preparing primary neuron cultures and M. Park (Stanford University) for helpful technical comments. We also thank the National Institute of Neurological Disorders and Stroke Light Imaging Facility, particularly C. Smith. In addition, we would like to acknowledge the National Institute of Neurological Disorders and Stroke sequencing facility. This research was supported by the National Cancer Institute Intramural Research Program (P.A.R.), the National Institute of Neurological Disorders and Stroke Intramural Research Program (Y.H.S. and K.W.R.), the Integrative Neural Immune Program (Y.H.S. fellowship), and the intramural program of the National Institute on Deafness and other Communication Disorders (R.S.P. and R.J.W.).

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Authors and Affiliations

  1. Receptor Biology Section, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, USA

    Young Ho Suh & Katherine W Roche

  2. Experimental Immunology Branch, National Cancer Institute, Bethesda, Maryland, USA

    Young Ho Suh & Paul A Roche

  3. Developmental Synaptic Plasticity Section, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, USA

    Akira Terashima & John T R Isaac

  4. National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland, USA

    Ronald S Petralia & Robert J Wenthold

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  1. Young Ho Suh
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Contributions

P.A.R. and K.W.R. designed and supervised the experiments and wrote the manuscript. Immunogold electron microscopy was performed by R.S.P. and R.J.W. The electrophysiology study was carried out by A.T. and J.T.R.I. All other experiments were performed by Y.H.S.

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Correspondence to Katherine W Roche or Paul A Roche.

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Suh, Y., Terashima, A., Petralia, R. et al. A neuronal role for SNAP-23 in postsynaptic glutamate receptor trafficking. Nat Neurosci 13, 338–343 (2010). https://doi.org/10.1038/nn.2488

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