The human brain is made up of an extensive network of neurons that communicate by forming specialized connections called synapses. The amount, location, and dynamic turnover of synaptic proteins, including neurotransmitter receptors and synaptic scaffolding molecules, are under complex regulation and play a crucial role in synaptic connectivity and plasticity, as well as in higher brain functions. An increasing number of studies have established ubiquitination and proteasome-mediated degradation as universal mechanisms in the control of synaptic protein homeostasis. In this paper, we focus on the role of the ubiquitin-proteasome system (UPS) in the turnover of major neurotransmitter receptors, including glutamatergic and nonglutamatergic receptors, as well as postsynaptic receptor-interacting proteins. 1. Introduction Neurons are highly complex cells that form a network of connectivity throughout the brain via specialized structures called synapses. The human brain contains approximately 85–100 billion neurons that can generate an estimated 100 trillion synapses [1]. These synapses maintain a careful balance between network plasticity and stability through finely controlled mechanisms such as intracellular trafficking and posttranslational modification of synaptic proteins. One such modification is ubiquitination, which is known to play a role in synaptic physiology and synapse formation, as well as in synaptic protein trafficking, stability, internalization, and degradation [2]. Malfunction of the ubiquitin system is also involved in the development of brain disorders such as autism, Alzheimer’s disease, Huntington’s disease, amyotrophic lateral sclerosis (ALS), and Parkinson’s disease [3]. Ubiquitin (Ub) is a small, highly conserved protein expressed in all eukaryotic cells that modulates an extensive range of biological functions including DNA repair, transcription, endocytosis, autophagy, and protein degradation. Structurally, ubiquitin is an 8.5？kDa, 76 amino acid polypeptide that forms a compact structure with an exposed carboxy terminal tail containing a diglycine motif that can be covalently ligated via an isopeptide bond to the primary ε-amino group of lysine (Lys) residues on a target substrate. This occurs through an enzymatic process termed ubiquitination, a reversible posttranslational modification that can affect the structure and activity of the targeted protein, along with its localization and binding interaction to other partners. The first step of this pathway involves the biochemical priming of ubiquitin by the E1 ubiquitin-activating
References
[1]
R. W. Williams and K. Herrup, “The control of neuron number,” Annual Review of Neuroscience, vol. 11, pp. 423–453, 1988.
[2]
J. J. Yi and M. D. Ehlers, “Emerging roles for ubiquitin and protein degradation in neuronal function,” Pharmacological Reviews, vol. 59, no. 1, pp. 14–39, 2007.
[3]
A. M. Mabb and M. D. Ehlers, “Ubiquitination in postsynaptic function and plasticity,” Annual Review of Cell and Developmental Biology, vol. 26, pp. 179–210, 2010.
[4]
A. L. Haas and I. A. Rose, “The mechanism of ubiquitin activating enzyme. A kinetic and equilibrium analysis,” Journal of Biological Chemistry, vol. 257, no. 17, pp. 10329–10337, 1982.
[5]
A. Hershko, H. Heller, S. Elias, and A. Ciechanover, “Components of ubiquitin-protein ligase system. Resolution, affinity purification, and role in protein breakdown,” Journal of Biological Chemistry, vol. 258, no. 13, pp. 8206–8214, 1983.
[6]
C. M. Pickart, “Mechanisms underlying ubiquitination,” Annual Review of Biochemistry, vol. 70, pp. 503–533, 2001.
[7]
H. C. Ardley and P. A. Robinson, “E3 ubiquitin ligases,” Essays in Biochemistry, vol. 41, pp. 15–30, 2005.
[8]
D. Rotin and S. Kumar, “Physiological functions of the HECT family of ubiquitin ligases,” Nature Reviews Molecular Cell Biology, vol. 10, no. 6, pp. 398–409, 2009.
[9]
K. D. Wilkinson, “Ubiquitination and deubiquitination: targeting of proteins for degradation by the proteasome,” Seminars in Cell and Developmental Biology, vol. 11, no. 3, pp. 141–148, 2000.
[10]
D. Komander, M. J. Clague, and S. Urbé, “Breaking the chains: structure and function of the deubiquitinases,” Nature Reviews Molecular Cell Biology, vol. 10, no. 8, pp. 550–563, 2009.
[11]
K. Husnjak and I. Dikic, “Ubiquitin-binding proteins: decoders of ubiquitin-mediated cellular functions,” Annual Review of Biochemistry, vol. 81, pp. 291–322, 2012.
[12]
F. Ikeda and I. Dikic, “Atypical ubiquitin chains: new molecular signals. 'Protein Modifications: beyond the Usual Suspects' Review Series,” EMBO Reports, vol. 9, no. 6, pp. 536–542, 2008.
[13]
M. D. Ehlers, “Activity level controls postsynaptic composition and signaling via the ubiquitin-proteasome system,” Nature Neuroscience, vol. 6, no. 3, pp. 231–242, 2003.
[14]
O. M. Schlüter, W. Xu, and R. C. Malenka, “Alternative N-terminal domains of PSD-95 and SAP97 govern activity-dependent regulation of synaptic AMPA receptor function,” Neuron, vol. 51, no. 1, pp. 99–111, 2006.
[15]
M. Colledge, E. M. Snyder, R. A. Crozier et al., “Ubiquitination regulates PSD-95 degradation and AMPA receptor surface expression,” Neuron, vol. 40, no. 3, pp. 595–607, 2003.
[16]
B. Bingol and E. M. Schuman, “A proteasome-sensitive connection between PSD-95 and GluR1 endocytosis,” Neuropharmacology, vol. 47, no. 5, pp. 755–763, 2004.
[17]
M. J. Bianchetta, T. T. Lam, S. N. Jones, and M. A. Morabito, “Cyclin-dependent kinase 5 regulates PSD-95 ubiquitination in neurons,” The Journal of Neuroscience, vol. 31, pp. 12029–12035, 2011.
[18]
S. H. Lee, L. Liu, Y. T. Wang, and M. Sheng, “Clathrin adaptor AP2 and NSF interact with overlapping sites of GluR2 and play distinct roles in AMPA receptor trafficking and hippocampal LTD,” Neuron, vol. 36, no. 4, pp. 661–674, 2002.
[19]
H. Dong, R. J. O'Brien, E. T. Fung, A. A. Lanahan, P. F. Worley, and R. L. Huganir, “GRIP: a synaptic PDZ domain-containing protein that interacts with AMPA receptors,” Nature, vol. 386, no. 6622, pp. 279–284, 1997.
[20]
L. Guo and Y. Wang, “Glutamate stimulates glutamate receptor interacting protein 1 degradation by ubiquitin-proteasome system to regulate surface expression of GluR2,” Neuroscience, vol. 145, no. 1, pp. 100–109, 2007.
[21]
M. Sheng and E. Kim, “The Shank family of scaffold proteins,” Journal of Cell Science, vol. 113, no. 11, pp. 1851–1856, 2000.
[22]
A. Y. Hung, C. C. Sung, I. L. Brito, and M. Sheng, “Degradation of postsynaptic scaffold GKAP and regulation of dendritic spine morphology by the TRIM3 ubiquitin ligase in rat hippocampal neurons,” PloS ONE, vol. 5, no. 3, Article ID e9842, 2010.
[23]
M. A. Bangash, J. M. Park, T. Melnikova et al., “Enhanced polyubiquitination of shank3 and NMDA receptor in a mouse model of autism,” Cell, vol. 145, no. 5, pp. 758–772, 2011.
[24]
J. Xia, X. Zhang, J. Staudinger, and R. L. Huganir, “Clustering of AMPA receptors by the synaptic PD domain-containing protein PICK1,” Neuron, vol. 22, no. 1, pp. 179–187, 1999.
[25]
K. L. Madsen, T. Beuming, M. Y. Niv et al., “Molecular determinants for the complex binding specificity of the PDZ domain in PICK1,” Journal of Biological Chemistry, vol. 280, no. 21, pp. 20539–20548, 2005.
[26]
M. Joch, A. R. Ase, C. X. Q. Chen et al., “Parkin-mediated monoubiquitination of the PDZ protein PICK1 regulates the activity of acid-sensing ion channels,” Molecular Biology of the Cell, vol. 18, no. 8, pp. 3105–3118, 2007.
[27]
D. T. S. Pak, S. Yang, S. Rudolph-Correia, E. Kim, and M. Sheng, “Regulation of dendritic spine morphology by SPAR, a PSD-95-associated RapGAP,” Neuron, vol. 31, no. 2, pp. 289–303, 2001.
[28]
D. T. S. Pak and M. Sheng, “Targeted protein degradation and synapse remodeling by an inducible protein kinase,” Science, vol. 302, no. 5649, pp. 1368–1373, 2003.
[29]
X. L. Ang, D. P. Seeburg, M. Sheng, and J. W. Harper, “Regulation of postsynaptic RapGAP SPAR by polo-like kinase 2 and the SCFβ-TRCP ubiquitin ligase in hippocampal neurons,” Journal of Biological Chemistry, vol. 283, no. 43, pp. 29424–29432, 2008.
[30]
I. M. González-González, N. García-Tardón, C. Giménez, and F. Zafra, “PKC-dependent endocytosis of the GLT1 glutamate transporter depends on ubiquitylation of lysines located in a C-terminal cluster,” Glia, vol. 56, no. 9, pp. 963–974, 2008.
[31]
A. L. Sheldon, M. I. González, E. N. Krizman-Genda, B. T. S. Susarla, and M. B. Robinson, “Ubiquitination-mediated internalization and degradation of the astroglial glutamate transporter, GLT-1,” Neurochemistry International, vol. 53, no. 6–8, pp. 296–308, 2008.
[32]
N. Garcia-Tardon, I. M. Gonzalez-Gonzalez, J. Martinez-Villarreal, E. Fernandez-Sanchez, C. Gimenez, et al., “Protein kinase C, (PKC)-promoted endocytosis of glutamate transporter GLT-1 requires ubiquitin ligase Nedd4-2-dependent ubiquitination but not phosphorylation,” The Journal of Biological Chemistry, vol. 287, pp. 19177–19187, 2012.
[33]
J. Martinez-Villarreal, N. Garcia Tardon, I. Ibanez, C. Gimenez, and F. Zafra, “Cell surface turnover of the glutamate transporter GLT-1 is mediated by ubiquitination/deubiquitination,” Glia, vol. 60, pp. 1356–1365, 2012.
[34]
K. Ishikawa, S. R. Nash, A. Nishimune, A. Neki, S. Kaneko, and S. Nakanishi, “Competitive interaction of seven in absentia homolog-1A and Ca2+/calmodulin with the cytoplasmic tail of group 1 metabotropic glutamate receptors,” Genes to Cells, vol. 4, no. 7, pp. 381–390, 1999.
[35]
K. Moriyoshi, K. Iijima, H. Fujii, H. Ito, Y. Cho, and S. Nakanishi, “Seven in absentia homolog 1A mediates ubiquitination and degradation of group 1 metabotropic glutamate receptors,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 23, pp. 8614–8619, 2004.
[36]
K. Rezvani, K. Baalman, Y. Teng, M. P. Mee, S. P. Dawson, et al., “Proteasomal degradation of the metabotropic glutamate receptor 1alpha is mediated by Homer-3 via the proteasomal S8 ATPase: signal transduction and synaptic transmission,” Journal of Neurochemistry, vol. 122, pp. 24–37, 2012.
[37]
G. D. Salinas, L. A. C. Blair, L. A. Needleman et al., “Actinfilin is a Cul3 substrate adaptor, linking GluR6 kainate receptor subunits to the ubiquitin-proteasome pathway,” Journal of Biological Chemistry, vol. 281, no. 52, pp. 40164–40173, 2006.
[38]
J. Marshall, L. A. C. Blair, and J. D. Singer, “BTB-kelch proteins and ubiquitination of kainate receptors,” Advances in Experimental Medicine and Biology, vol. 717, pp. 115–125, 2011.
[39]
S. Martin, A. Nishimune, J. R. Mellor, and J. M. Henley, “SUMOylation regulates kainate-receptor-mediated synaptic transmission,” Nature, vol. 447, no. 7142, pp. 321–325, 2007.
[40]
S. E. Chamberlain, I. M. Gonzalez-Gonzalez, K. A. Wilkinson, et al., “SUMOylation and phosphorylation of GluK2 regulate kainate receptor trafficking and synaptic plasticity,” Nature Neuroscience, vol. 15, pp. 845–852, 2012.
[41]
K. A. Wilkinson, F. Konopacki, and J. M. Henley, “Modification and movement: phosphorylation and SUMOylation regulate endocytosis of GluK2-containing kainate receptors,” Communicative & Integrative Biology, vol. 5, pp. 223–226, 2012.
[42]
F. A. Konopacki, N. Jaafari, D. L. Rocca, K. A. Wilkinson, S. Chamberlain, et al., “Agonist-induced PKC phosphorylation regulates GluK2 SUMOylation and kainate receptor endocytosis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, pp. 19772–19777, 2011.
[43]
Q. J. Zhu, Y. Xu, C. P. Du, and X. Y. Hou, “SUMOylation of the kainate receptor subunit GluK2 contributes to the activation of the MLK3-JNK3 pathway following kainate stimulation,” FEBS Letters, vol. 586, pp. 1259–1264, 2012.
[44]
A. Kato, N. Rouach, R. A. Nicoll, and D. S. Bredt, “Activity-dependent NMDA receptor degradation mediated by retrotranslocation and ubiquitination,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 15, pp. 5600–5605, 2005.
[45]
R. F. Nelson, K. A. Glenn, V. M. Miller, H. Wen, and H. L. Paulson, “A novel route for F-box protein-mediated ubiquitination links CHIP to glycoprotein quality control,” Journal of Biological Chemistry, vol. 281, no. 29, pp. 20242–20251, 2006.
[46]
R. Jurd, C. Thornton, J. Wang et al., “Mind bomb-2 is an E3 ligase that ubiquitinates the N-methyl-D-aspartate receptor NR2B subunit in a phosphorylation-dependent manner,” Journal of Biological Chemistry, vol. 283, no. 1, pp. 301–310, 2008.
[47]
M. Burbea, L. Dreier, J. S. Dittman, M. E. Grunwald, and J. M. Kaplan, “Ubiquitin and AP180 regulate the abundance of GLR-1 glutamate receptors at postsynaptic elements in C. elegans,” Neuron, vol. 35, no. 1, pp. 107–120, 2002.
[48]
P. Juo and J. M. Kaplan, “The anaphase-promoting complex regulates the abundance of GLR-1 glutamate receptors in the ventral nerve cord of C. elegans,” Current Biology, vol. 14, no. 22, pp. 2057–2062, 2004.
[49]
H. Schaefer and C. Rongo, “KEL-8 is a substrate receptor for CUL3-dependent ubiquitin ligase that regulates synaptic glutamate receptor turnover,” Molecular Biology of the Cell, vol. 17, no. 3, pp. 1250–1260, 2006.
[50]
E. C. Park, D. R. Glodowski, and C. Rongo, “The ubiquitin ligase RPM-1 and the p38 MAPK PMK-3 regulate AMPA receptor trafficking,” PLoS ONE, vol. 4, no. 1, Article ID e4284, 2009.
[51]
L. Dreier, M. Burbea, and J. M. Kaplan, “LIN-23-mediated degradation of β-catenin regulates the abundance of GLR-1 glutamate receptors in the ventral nerve cord of C. elegans,” Neuron, vol. 46, no. 1, pp. 51–64, 2005.
[52]
K. Rezvani, Y. Teng, D. Shim, and M. De Biasi, “Nicotine regulates multiple synaptic proteins by inhibiting proteasomal activity,” Journal of Neuroscience, vol. 27, no. 39, pp. 10508–10519, 2007.
[53]
D. Zhang, Q. Hou, M. Wang et al., “Na, K-ATPase activity regulates AMPA receptor turnover through proteasome-mediated proteolysis,” Journal of Neuroscience, vol. 29, no. 14, pp. 4498–4511, 2009.
[54]
G. N. Patrick, B. Bingol, H. A. Weld, and E. M. Schuman, “Ubiquitin-mediated proteasome activity is required for agonist-induced endocytosis of GluRs,” Current Biology, vol. 13, no. 23, pp. 2073–2081, 2003.
[55]
L. A. Schwarz, B. J. Hall, and G. N. Patrick, “Activity-dependent ubiquitination of GluA1 mediates a distinct AMPA receptor endocytosis and sorting pathway,” Journal of Neuroscience, vol. 30, no. 49, pp. 16718–16729, 2010.
[56]
M. P. Lussier, Y. Nasu-Nishimura, and K. W. Roche, “Activity-dependent ubiquitination of the AMPA receptor subunit GluA2,” Journal of Neuroscience, vol. 31, no. 8, pp. 3077–3081, 2011.
[57]
A. Lin, Q. Hou, L. Jarzylo, S. Amato, J. Gilbert, et al., “Nedd4-mediated AMPA receptor ubiquitination regulates receptor turnover and trafficking,” Journal of Neurochemistry, vol. 119, pp. 27–39, 2011.
[58]
A. K. Y. Fu, K. W. Hung, W. Y. Fu et al., “APCCdh1 mediates EphA4-dependent downregulation of AMPA receptors in homeostatic plasticity,” Nature Neuroscience, vol. 14, no. 2, pp. 181–191, 2011.
[59]
J. R. Kowalski, C. L. Dahlberg, and P. Juo, “The deubiquitinating enzyme USP-46 negatively regulates the degradation of glutamate receptors to control their abundance in the ventral nerve cord of Caenorhabditis elegans,” Journal of Neuroscience, vol. 31, no. 4, pp. 1341–1354, 2011.
[60]
S. Suzuki, K. Tamai, M. Watanabe et al., “AMSH is required to degrade ubiquitinated proteins in the central nervous system,” Biochemical and Biophysical Research Communications, vol. 408, no. 4, pp. 582–588, 2011.
[61]
T. C. Jacob, S. J. Moss, and R. Jurd, “GABAA receptor trafficking and its role in the dynamic modulation of neuronal inhibition,” Nature Reviews Neuroscience, vol. 9, no. 5, pp. 331–343, 2008.
[62]
R. S. Saliba, G. Michels, T. C. Jacob, M. N. Pangalos, and S. J. Moss, “Activity-dependent ubiquitination of GABAA receptors regulates their accumulation at synaptic sites,” Journal of Neuroscience, vol. 27, no. 48, pp. 13341–13351, 2007.
[63]
R. S. Saliba, Z. Gu, Z. Yan, and S. J. Moss, “Blocking L-type voltage-gated Ca2+ channels with dihydropyridines reduces γ-aminobutyric acid type A receptor expression and synaptic inhibition,” Journal of Biological Chemistry, vol. 284, no. 47, pp. 32544–32550, 2009.
[64]
F. K. Bedford, J. T. Kittler, E. Muller et al., “GABAA receptor cell surface number and subunit stability are regulated by the ubiquitin-like protein Plic-1,” Nature Neuroscience, vol. 4, no. 9, pp. 908–916, 2001.
[65]
R. S. Saliba, M. Pangalos, and S. J. Moss, “The ubiquitin-like protein plic-1 enhances the membrane insertion of GABAA receptors by increasing their stability within the endoplasmic reticulum,” Journal of Biological Chemistry, vol. 283, no. 27, pp. 18538–18544, 2008.
[66]
I. L. Arancibia-Cárcamo, E. Y. Yuen, J. Muir et al., “Ubiquitin-dependent lysosomal targeting of GABAA receptors regulates neuronal inhibition,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 41, pp. 17552–17557, 2009.
[67]
T. Grampp, K. Sauter, B. Markovic, and D. Benke, “γ-Aminobutyric acid type B receptors are constitutively internalized via the clathrin-dependent pathway and targeted to lysosomes for degradation,” Journal of Biological Chemistry, vol. 282, no. 33, pp. 24157–24165, 2007.
[68]
K. Rezvani, Y. Teng, and M. De Biasi, “The ubiquitin-proteasome system regulates the stability of neuronal nicotinic acetylcholine receptors,” Journal of Molecular Neuroscience, vol. 40, no. 1-2, pp. 177–184, 2010.
[69]
H. Betz and B. Laube, “Glycine receptors: recent insights into their structural organization and functional diversity,” Journal of Neurochemistry, vol. 97, no. 6, pp. 1600–1610, 2006.
[70]
C. Büttner, S. Sadtler, A. Leyendecker et al., “Ubiquitination precedes internalization and proteolytic cleavage of plasma membrane-bound glycine receptors,” Journal of Biological Chemistry, vol. 276, no. 46, pp. 42978–42985, 2001.
[71]
E. Fernández-Sánchez, J. Martínez-Villarreal, C. Giménez, and F. Zafra, “Constitutive and regulated endocytosis of the glycine transporter GLYT1b is controlled by ubiquitination,” Journal of Biological Chemistry, vol. 284, no. 29, pp. 19482–19492, 2009.
[72]
P. Rondou, G. Haegeman, P. Vanhoenacker, and K. Van Craenenbroeck, “BTB protein KLHL12 targets the dopamine D4 receptor for ubiquitination by a Cul3-based E3 ligase,” Journal of Biological Chemistry, vol. 283, no. 17, pp. 11083–11096, 2008.
[73]
P. Rondou, K. Skieterska, A. Packeu et al., “KLHL12-mediated ubiquitination of the dopamine D4 receptor does not target the receptor for degradation,” Cellular Signalling, vol. 22, no. 6, pp. 900–913, 2010.
[74]
O. J. Kim, “A single mutation at lysine 241 alters expression and trafficking of the D2 dopamine receptor,” Journal of Receptors and Signal Transduction, vol. 28, no. 5, pp. 453–464, 2008.
[75]
A. N. Hegde, “Ubiquitin-proteasome-mediated local protein degradation and synaptic plasticity,” Progress in Neurobiology, vol. 73, no. 5, pp. 311–357, 2004.
[76]
G. N. Patrick, “Synapse formation and plasticity: recent insights from the perspective of the ubiquitin proteasome system,” Current Opinion in Neurobiology, vol. 16, no. 1, pp. 90–94, 2006.
