Skip to main content
Log in

Running to stand still

Ionotropic receptor dynamics at central and peripheral synapses

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

For synapses to form and function, neurotransmitter receptors must be recruited to a location on the postsynaptic cell in direct apposition to presynaptic neurotransmitter release. However, once receptors are inserted into the postsynaptic membrane, they are not fixed in place but are continually exchanged between synaptic and extrasynaptic regions, and they cycle between the surface and intracellular compartments. This article highlights and compares the current knowledge about the dynamics of acetylcholine receptors at the vertebrate peripheral neuromuscular junction and AMPA, N-methyl-d-aspartate, and γ-aminobutyric acid receptors in central synapses.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Malenka R. C. (2003) Synaptic plasticity and AMPA receptor trafficking. Ann. NY Acad. Sci. 1003, 1–11.

    Article  PubMed  CAS  Google Scholar 

  2. Collingridge G. L., Isaac J. T., and Wang Y. T. (2004) Receptor trafficking and synaptic plasticity. Nat. Rev. Neurosci. 5, 952–962.

    Article  PubMed  CAS  Google Scholar 

  3. Bredt D. S. and Nicoll R. A. (2003) AMPA receptor trafficking at excitatory synapses. Neuron 40, 361–379.

    Article  PubMed  CAS  Google Scholar 

  4. Bliss T. V. and Lomo T. (1973) Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path. J. Physiol. 232, 331–356.

    PubMed  CAS  Google Scholar 

  5. Bear M. F. and Malenka R. C. (1994) Synaptic plasticity: LTP and LTD. Curr. Opin. Neurobiol. 4, 389–399.

    Article  PubMed  CAS  Google Scholar 

  6. Hollmann M. and Heinemann S. (1994) Cloned glutamate receptors. Annu. Rev. Neurosci. 17, 31–108.

    Article  PubMed  CAS  Google Scholar 

  7. Zhu J. J., Esteban J. A., Hayashi Y., and Malinow R. (2000) Postnatal synaptic potentiation: delivery of GluR4-containing AMPA receptors by spontaneous activity. Nat. Neurosci. 3, 1098–1106.

    Article  PubMed  CAS  Google Scholar 

  8. Huh K. H. and Wenthold R. J. (1999) Turnover analysis of glutamate receptors identifies a rapidly degraded pool of the N-methyl-D-aspartate receptor subunit, NR1, in cultured cerebellar granule cells. J. Biol. Chem. 274, 151–157.

    Article  PubMed  CAS  Google Scholar 

  9. Archibald K., Perry M. J., Molnar E., and Henley J. M. (1998) Surface expression and metabolic half-life of AMPA receptors in cultured rat cerebellar granule cells. Neuropharmacology 37, 1345–1353.

    Article  PubMed  CAS  Google Scholar 

  10. Mammen A. L., Huganir R. L., and O'Brien R. J. (1997) Redistribution and stabilization of cell surface glutamate receptors during synapse formation. J. Neurosci. 17, 7351–7358.

    PubMed  CAS  Google Scholar 

  11. O'Brien, R. J., Kamboj, S., Ehlers, M. D., Rosen, K. R., Fischbach, G. D., and Huganir, R. L. (1998) Activity-dependent modulation of synaptic AMPA receptor accumulation. Neuron 21, 1067–1078.

    Article  PubMed  Google Scholar 

  12. Ehlers M. D. (2000) Reinsertion or degradation of AMPA receptors determined by activity-dependent endocytic sorting. Neuron 28, 511–525.

    Article  PubMed  CAS  Google Scholar 

  13. Park M., Penick E. C., Edwards, J. G., Kauer J. A., and Ehlers M. D. (2004) Recycling endosomes supply AMPA receptors for LTP. Science 305, 1972–1975.

    Article  PubMed  CAS  Google Scholar 

  14. Passafaro M., Piech V., and Sheng M. (2001) Subunit-specific temporal and spatial patterns of AMPA receptor exocytosis in hippocampal neurons. Nat. Neurosci. 4, 917–926.

    Article  PubMed  CAS  Google Scholar 

  15. Lin, J. W., Ju, W., Foster, K., et al. (2000) Distinct molecular mechanisms and divergent endocytotic pathways of AMPA receptor internalization. Nat. Neurosci. 3, 1282–1290.

    Article  PubMed  CAS  Google Scholar 

  16. Sekine-Aizawa Y. and Huganir R. L. (2004) Imaging of receptor trafficking by using alpha-bungarotoxin-binding-site-tagged receptors. Proc. Natl. Acad. Sci. USA 101, 17,114–17,119.

    Article  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  19. Lee S. H., Simonetta A., and Sheng M. (2004) Subunit rules governing the sorting of internalized AMPA receptors in hippocampal neurons. Neuron 43, 221–236.

    Article  PubMed  CAS  Google Scholar 

  20. Nishimune, A., Isaac, J. T., Molnar, E., et al. (1998) NSF binding to GluR2 regulates synaptic transmission. Neuron 21, 87–97.

    Article  PubMed  CAS  Google Scholar 

  21. Adesnik, H., Nicoll R. A., and England P. M. (2005) Photoinactivation of native AMPA receptors reveals their real-time trafficking. Neuron 48, 977–985.

    Article  PubMed  CAS  Google Scholar 

  22. Gomes A. R., Correia S. S., Carvalho A. L., and Duarte C. B. (2003) Regulation of AMPA receptor activity, synaptic targeting and recycling: role in synaptic plasticity. Neurochem. Res. 28, 1459–1473.

    Article  PubMed  CAS  Google Scholar 

  23. Palmer C. L., Cotton, L., and Henley J. M. (2005) The molecular pharmacology and cell biology of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors. Pharmacol. Rev. 57, 253–277.

    Article  PubMed  CAS  Google Scholar 

  24. Shi, S., Hayashi, Y., Esteban, J. A., and Malinow, R. (2001) Subunit-specific rules governing AMPA receptor trafficking to synapses in hippocampal pyramidal neurons. Cell 105, 331–343.

    Article  PubMed  CAS  Google Scholar 

  25. Hayashi, Y., Shi, S. H., Esteban, J. A., Piccini, A., Poncer, J. C., and Malinow, R. (2000) Driving AMPA receptors into synapses by LTP and CaMKII: requirement for GluR1 and PDZ domain interaction. Science 287, 2262–2267.

    Article  PubMed  CAS  Google Scholar 

  26. Shi, S. H., Hayashi, Y., Petralia, R. S., et al. (1999) Rapid spine delivery and redistribution of AMPA receptors after synaptic NMDA receptor activation. Science 284, 1811–1816.

    Article  PubMed  CAS  Google Scholar 

  27. Lu, W., Man, H., Ju, W., Trimble, W. S., Mac-Donald, J. F., and Wang, Y. T. (2001) Activation of synaptic NMDA receptors induces membrane insertion of new AMPA receptors and LTP in cultured hippocampal neurons. Neuron 29, 243–254.

    Article  PubMed  CAS  Google Scholar 

  28. Lee S. H., Liu L., Wang Y. T., and Sheng M. (2002) Clathrin adaptor AP2 and NSF interact with overlapping sites of GluR2 and play distinct roles in AMPA receptor trafficking and hippocampal LTD. Neuron 36, 661–674.

    Article  PubMed  CAS  Google Scholar 

  29. Brown T. C., Tran I. C., Backos D. S., and Esteban J. A. (2005) NMDA receptor-dependent activation of the small GTPase Rab5 drives the removal of synaptic AMPA receptors during hippocampal LTD. Neuron 45, 81–94.

    Article  PubMed  CAS  Google Scholar 

  30. Jia, Z., Agopyan, N., Miu, P., et al. (1996) Enhanced LTP in mice deficient in the AMPA receptor GluR2. Neuron 17, 945–956.

    Article  PubMed  CAS  Google Scholar 

  31. Meng Y., Zhang Y., and Jia Z. (2003) Synaptic transmission and plasticity in the absence of AMPA glutamate receptor GluR2 and GluR3. Neuron 39, 163–176.

    Article  PubMed  CAS  Google Scholar 

  32. Zamanillo D., Sprengel, R., Hvalby, O., et al. (1999) Importance of AMPA receptors for hippocampal synaptic plasticity but not for spatial learning. Science 284, 1805–1811.

    Article  PubMed  CAS  Google Scholar 

  33. Reisel, D., Bannerman, D. M., Schmitt, W. B., et al. (2002) Spatial memory dissociations in mice lacking GluR1. Nat. Neurosci. 5, 868–873.

    Article  PubMed  CAS  Google Scholar 

  34. Schmitt W. B., Deacon R. M., Seeburg P. H., Rawlins J. N., and Bannerman D. M. (2003) A within-subjects, within-task demonstration of intact spatial reference memory and impaired spatial working memory in glutamate receptor-A-deficient mice. J. Neurosci. 23, 3953–3959.

    PubMed  CAS  Google Scholar 

  35. Schmitt, W. B., Sprengel, R., Mack, V., et al. (2005). Restoration of spatial working memory by genetic rescue of GluR-A-deficient mice. Nat. Neurosci. 8, 270–272.

    Article  PubMed  CAS  Google Scholar 

  36. Rumpel S., LeDoux J., Zador A., and Malinow R. (2005) Postsynaptic receptor trafficking underlying a form of associative learning. Science 308, 83–88.

    Article  PubMed  CAS  Google Scholar 

  37. Heynen, A. J., Yoon, B. J., Liu, C. H., Chung, H. J., Huganir, R. L., and Bear, M. F. (2003) Molecular mechanism for loss of visual cortical responsiveness following brief monocular deprivation. Nat. Neurosci. 6, 854–862.

    Article  PubMed  CAS  Google Scholar 

  38. Takahashi, T., Svoboda K., and Malinow R. (2003) Experience strengthening transmission by driving AMPA receptors into synapses. Science 299, 1585–1588.

    Article  PubMed  CAS  Google Scholar 

  39. Schnell, E., Sizemore, M., Karimzadegan, S., Chen, L., Bredt, D. S., and Nicoll, R. A. (2002) Direct interactions between PSD-95 and stargazin control synaptic AMPA receptor numben. Proc. Natl. Acad. Sci. USA 99, 13,902–13,907.

    Article  CAS  Google Scholar 

  40. Nicoll R. A., Tomita S., and Bredt D. S. (2006) Auxiliary subunits assist AMPA-type glutamate receptors. Science 311, 1253–1256.

    Article  PubMed  CAS  Google Scholar 

  41. Chen, L., Chetkovich, D. M., Petralia, R. S., et al. (2000) Stargazin regulates synaptic targeting of AMPA receptors by two distinct mechanisms. Nature 408, 936–943.

    Article  PubMed  CAS  Google Scholar 

  42. Hashimoto, K., Fukaya, M., Qiao, X., Sakimura, K., Watanabe, M., and Kano, M. (1999) Impairment of AMPA receptor function in cerebellar granule cells of ataxic mutant mouse stargazer. J. Neurosci. 19, 6027–6036.

    PubMed  CAS  Google Scholar 

  43. Rouach, N., Byrd, K., Petralia, R. S., et al. (2005) TARP gamma-8 controls hippocampal AMPA receptor number, distribution and synaptic plasticity. Nat. Neurosci. 8, 1525–1533.

    Article  PubMed  CAS  Google Scholar 

  44. Tomita S., Stein V., Stocker T. J., Nicoll R. A., and Bredt D. S. (2005) Bidirectional synaptic plasticity regulated by phosphorylation of stargazin-like TARPs. Neuron 45, 269–277.

    Article  PubMed  CAS  Google Scholar 

  45. Tomita S., Fukata M., Nicoll R. A., and Bredt D. S. (2004) Dynamic interaction of stargazinlike TARPs with cycling AMPA receptors at synapses. Science 303, 1508–1511.

    Article  PubMed  CAS  Google Scholar 

  46. Tomita, S., Adesnik, H., Sekiguchi, M., et al. (2005) Stargazin modulates AMPA receptor gating and trafficking by distinct domains. Nature 435, 1052–1058.

    Article  PubMed  CAS  Google Scholar 

  47. Triller A. and Choquet D. (2003) Synaptic structure and diffusion dynamics of synaptic receptors. Biol. Cell. 95, 465–476.

    Article  PubMed  CAS  Google Scholar 

  48. Axelrod, D., Ravdin, P., Koppel, D. E., et al. (1976) Lateral motion of fluorescently labeled acetylcholine receptors in membranes of developing muscle fibers. Proc. Natl. Acad. Sci. USA 73, 4594–4598.

    Article  PubMed  CAS  Google Scholar 

  49. Blanpied T. A., Scott D. B., and Ehlers M. D. (2002) Dynamics and regulation of clathrin coats at specialized endocytic zones of dendrites and spines. Neuron 36, 435–449.

    Article  PubMed  CAS  Google Scholar 

  50. Ashby, M. C., De La Rue, S. A., Ralph, G. S., Uney, J., Collingridge, G. L., and Henley, J. M. (2004) Removal of AMPA receptors (AMPARs) from synapses is preceded by transient endocytosis of extrasynaptic AMPARs. J. Neurosci. 24, 5172–5176.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  52. Tardin C., Cognet L., Bats C., Lounis B., and Choquet D. (2003) Direct imaging of lateral movements of AMPA receptors inside synapses. EMBO J. 22, 4656–4665.

    Article  PubMed  CAS  Google Scholar 

  53. Groc, L., Heine, M., Cognet, L., et al. (2004) Differential activity-dependent regulation of the lateral mobilities of AMPA and NMDA receptors. Nat. Neurosci. 7, 695–696.

    Article  PubMed  CAS  Google Scholar 

  54. Hanley J. G., Khatri L., Hanson P. I., and Ziff E. B. (2002) NSF ATPase and alpha-/beta-SNAPs disassemble the AMPA receptor-PICK1 complex. Neuron 34, 53–67.

    Article  PubMed  CAS  Google Scholar 

  55. Braithwaite S. P., Xia H., and Malenka R. C. (2002) Differential roles for NSF and GRIP/ABP in AMPA receptor cycling. Proc. Natl. Acad. Sci. USA 99, 7096–7101.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  57. Dong, H., O'Brien, R. J., Fung, E. T., Lanahan, A. A., Worley, P. F., and Huganir, R. L. (1997) GRIP: a synaptic PDZ domain-containing protein that interacts with AMPA receptors. Nature 386, 279–284.

    Article  PubMed  CAS  Google Scholar 

  58. Hanley J. G. and Henley J. M. (2005) PICK1 is a calcium-sensor for NMDA-induced AMPA receptor trafficking. EMBO J. 24, 3266–3278.

    Article  PubMed  CAS  Google Scholar 

  59. Lu W. and Ziff E. B. (2005) PICK1 interacts with ABP/GRIP to regulate AMPA receptor trafficking. Neuron 47, 407–421.

    Article  PubMed  CAS  Google Scholar 

  60. Perez, J. L., Khatri, L., Chang, C., Srivastava, S., Osten, P., and Ziff, E. B. (2001) PICK1 targets activated protein kinase Calpha to AMPA receptor clusters in spines of hippocampal neurons and reduces surface levels of the AMPA-type glutamate receptor subunit 2. J. Neurosci. 21, 5417–5428.

    PubMed  CAS  Google Scholar 

  61. Seidenman K. J., Steinberg J. P., Huganir R., and Malinow R. (2003) Glutamate receptor subunit 2 Serine 880 phosphorylation modulates synaptic transmission and mediates plasticity in CA1 pyramidal cells. J. Neurosci. 23, 9220–9228.

    PubMed  CAS  Google Scholar 

  62. Chung H. J., Steinberg J. P., Huganir R. L., and Linden D. J. (2003) Requirement of AMPA receptor GluR2 phosphorylation for cerebellar long-term depression. Science 300, 1751–1755.

    Article  PubMed  CAS  Google Scholar 

  63. Chung H. J., Xia J., Scannevin R. H., Zhang, X., and Huganir R. L. (2000) Phosphorylation of the AMPA receptor subunit GluR2 differentially regulates its interaction with PDZ domain-containing proteins. J. Neurosci. 20, 7258–7267.

    PubMed  CAS  Google Scholar 

  64. Hayashi T. and Huganir R. L. (2004) Tyrosine phosphorylation and regulation of the AMPA receptor by SRC family tyrosine kinases. J. Neurosci. 24, 6152–6160.

    Article  PubMed  CAS  Google Scholar 

  65. Leonard A. S., Davare M. A., Horne M. C., Garner C. C., and Hell J. W. (1998) SAP97 is associated with the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor GluR1 subunit. J. Biol. Chem. 273, 19,518–19,524.

    CAS  Google Scholar 

  66. Valtschanoff, J. G., Burette, A., Davare, M. A., Leonard, A. S., Hell, J. W., and Weinberg, R. J. (2000) SAP97 concentrates at the postsynaptic density in cerebral cortex. Eur. J. Neurosci. 12, 3605–3614.

    Article  PubMed  CAS  Google Scholar 

  67. Gardoni, F., Mauceri, D., Fiorentini, C., et al. (2003) CaMKII-dependent phosphorylation regulates SAP97/NR2A interaction. J. Biol. Chem. 278, 44,745–44,752.

    Article  CAS  Google Scholar 

  68. Jin W., Ge, W. P., Xu, J., et al (2006) Lipid binding regulates synaptic targeting of PICK1, AMPA receptor trafficking, and synaptic plasticity. J. Neurosci. 26, 2380–2390.

    Article  PubMed  CAS  Google Scholar 

  69. Rumbaugh, G., Sia, G. M., Garner, C. C., and Huganir, R. L. (2003) Synapse-associated protein-97 isoform-specific regulation of surface AMPA receptors and synaptic function in cultured neurons. J. Neurosci. 23, 4567–4576.

    PubMed  CAS  Google Scholar 

  70. Cai C., Li H., Rivera C. and Keinanen K. (2006) Interaction between SAP97 and PSD-95, two Maguk proteins involved in synaptic trafficking of AMPA receptors. J. Biol. Chem. 281, 4267–4273.

    Article  PubMed  CAS  Google Scholar 

  71. Mauceri D., Cattabeni F. Di Luca M., and Gardoni F. (2004) Calcium/calmodulin-dependent protein kinase II phosphorylation drives synapse-associated protein 97 into spines. J. Biol. Chem. 279, 23,813–23,821.

    Article  CAS  Google Scholar 

  72. Nakagawa, T., Futai, K., Lashuel, H. A., et al. (2004) Quaternary structure protein dynamics, and synaptic function of SAP97 controlled by L27 domain interactions. Neuron 44, 453–467.

    Article  PubMed  CAS  Google Scholar 

  73. Kim, C. H., Takamiya, K., Petralia, R. S., et al. (2005). Persistent hippocampal CA1 LTP in mice lacking the C-terminal PDZ ligand of GluR1. Nat. Neurosci. 8, 985–987.

    Article  PubMed  CAS  Google Scholar 

  74. Ehrlich I. and Malinow R. (2004) Postsynaptic density 95 controls AMPA receptor incorporation during long-term potentiation and experience-driven synaptic plasticity. J. Neurosci. 24, 916–927.

    Article  PubMed  CAS  Google Scholar 

  75. Tovar K. R. and Westbrook G. L. (1999) The incorporation of NMDA receptors with a distinct subunit composition at nascent hippocampal synapses in vitro. J. Neurosci. 19, 4180–4188.

    PubMed  CAS  Google Scholar 

  76. Kew J. N., Richards J. G., Mutel, V., and Kemp J. A. (1998) Developmental changes in NMDA receptor glycine affinity and ifenprodil sensitivity reveal three distinct populations of NMDA receptors in individual rat cortical neurons J. Neurosci. 18, 1935–1943.

    PubMed  CAS  Google Scholar 

  77. Rumbaugh G. and Vicini S. (1999) Distinct synaptic and extrasynaptic NMDA receptors in developing cerebellar granule neurons. J. Neurosci. 19, 10,603–10,610.

    CAS  Google Scholar 

  78. Vicini, S., Wang, J. F., Li, J. H., et al. (1998). Functional and pharmacological differences between recombinant N-methyl-d-aspartate receptors. J. Neurophysiol. 79, 555–566.

    PubMed  CAS  Google Scholar 

  79. Carroll, R. C. and Zukin, R. S. (2002) NMDA-receptor trafficking and targeting: implications for synaptic transmission and plasticity. Trends Neurosci. 25, 571–577.

    Article  PubMed  CAS  Google Scholar 

  80. Nong Y., Huang Y. Q., and Salter M. W. (2004) NMDA receptors are movin' in. Curr. Opin. Neurobiol. 14, 353–361.

    Article  PubMed  CAS  Google Scholar 

  81. Perez-Otano I. and Ehlers M. D. (2005) Homeostatic plasticity and NMDA receptor trafficking Trends Neurosci. 28, 229–238.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  83. Roche, K. W., Standley, S., McCallum, J., Dune Ly C., Ehlers, M. D., and Wenthold, R. J. (2001) Molecular determinants of NMDA receptor internalization. Nat. Neurosci. 4, 794–802.

    Article  PubMed  CAS  Google Scholar 

  84. Sharma K., Fong D. K., and Craig A. M. (2006) Postsynaptic protein mobility in dendritic spines: long-term regulation by synaptic NMDA receptor activation. Mol. Cell Neurosci. 31 702–712.

    Article  PubMed  CAS  Google Scholar 

  85. Nong, Y., Huang, Y. Q., Ju, W., et al. (2003) Glycine binding primes NMDA receptor internalization. Nature 422, 302–307.

    Article  PubMed  CAS  Google Scholar 

  86. Grosshans, D. R., Clayton, D. A., Coultrap, S. I., and Browning M. D. (2002) LTP leads to rapid surface expression of NMDA but not AMPA receptors in adult, rat CA1. Nat. Neurosci. 5, 27–33.

    Article  PubMed  CAS  Google Scholar 

  87. Quinlan E. M., Philpot, B. D., Huganir R. L., and Bear M. F. (1999) Rapid, experience dependent expression of synaptic NMDA receptors in visual cortex in vivo. Nat. Neurosci 2, 352–357.

    Article  PubMed  CAS  Google Scholar 

  88. Scott D. B., Blanpied T. A., Swanson, G. T., Zhang, C., and Ehlers M. D. (2001) An NMDA receptor ER retention signal regulated by phosphorylation and alternative splicing. J. Neurosci. 21, 3063–3072.

    PubMed  CAS  Google Scholar 

  89. Mu Y., Otsuka T., Horton A. C., Scott D. B., and Ehlers M. D. (2003) Activity-dependent mRNA splicing controls ER export and synaptic delivery of NMDA receptors. Neuron 40, 581–594.

    Article  PubMed  CAS  Google Scholar 

  90. Standley, S., Roche, K. W., McCallum, J., Sans N., and Wenthold R. J. (2000) PDZ domain suppression of an ER retention signal in NMDA receptor NR1 splice variants. Neuron 28, 887–898.

    Article  PubMed  CAS  Google Scholar 

  91. Xia H., Hornby Z. D., and Malenka, R. C. (2001) An ER retention signal explains differences in surface expression of NMDA and AMPA receptor subunits. Neuropharmacology 41, 714–723.

    Article  PubMed  CAS  Google Scholar 

  92. Scott D. B., Blanpied T. A., and Ehlers M. D. (2003) Coordinated PKA and PKC phosphorylation suppresses RXR-mediated ER retention and regulates the surface delivery of NMDA receptors. Neuropharmacology 45, 755–767.

    Article  PubMed  CAS  Google Scholar 

  93. Kim C. H., Chung H. J., Lee H. K., and Huganir, R. L. (2001) Interaction of the AMPA receptor subunit GluR2/3 with PDZ domains regulates hippocampal long-term depression. Proc. Natl. Acad. Sci. USA 98, 11,725–11,730.

    CAS  Google Scholar 

  94. Connolly, C. N., Kittler, J. T., Thomas, P., et al. (1999) Cell surface stability of gamma-aminobutyric acid type A receptors. Dependence on protein kinase C activity and subunit composition. J. Biol. Chem. 274, 36,565–36,572.

    Article  CAS  Google Scholar 

  95. Lan, J. Y., Skeberdis, V. A., Jover, T., et al. (2001) Protein kinase C modulates NMDA receptor trafficking and gating. Nat. Neurosci. 4, 382–390.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  98. Lau, L. F., Mammen, A., Ehlers, M. D., et al. (1996) Interaction of the N-methyl-d-aspartate receptor complex with a novel synapse associated protein, SAP102. J. Biol. Chem. 271, 21,622–21,628.

    CAS  Google Scholar 

  99. Muller, B. M., Kistner, U., Kindler, S., et al. (1996) SAP102, a novel postsynaptic protein that interacts with NMDA receptor complexes in vivo. Neuron 17, 255–265.

    Article  PubMed  CAS  Google Scholar 

  100. Sans, N., Wang, P. Y., Du, Q., et al. (2005) mPins modulates PSD-95 and SAP102 trafficking and influences NMDA receptor surface expression. Nat. Cell. Biol. 7, 1079–1090.

    Article  CAS  Google Scholar 

  101. Barria A. and Malinow R. (2002) Subunit-specific NMDA receptor trafficking to synapses. Neuron 35, 345–353.

    Article  PubMed  CAS  Google Scholar 

  102. Chung H. J., Huang Y. H., Lau L. F., and Huganir R. L. (2004) Regulation of the NMDA receptor complex and trafficking by activity-dependent phosphorylation of the NR2B subunit PDZ ligand. J. Neurosci. 24, 10,248–10,259.

    CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  104. Migaud, M., Charlesworth, P., Dempster, M., et al. (1998) Enhanced long-term potentiation and impaired learning in mice with mutant postsynaptic density-95 protein. Nature 396, 433–439.

    Article  PubMed  CAS  Google Scholar 

  105. Lavezzari G., McCallum J., Lee R., and Roche K. W. (2003) Differential binding of the AP-2 adaptor complex and PSD-95 to the C-terminus of the NMDA receptor subunit NR2B regulates surface expression. Neuropharmacology 45, 729–737.

    Article  PubMed  CAS  Google Scholar 

  106. Prybylowski, K., Chang, K., Sans, N., Kan L., Vicini, S., and Wenthold, R. J. (2005) The synaptic localization of NR2B-containing NMDA receptors is controlled by interactions with PDZ proteins and AP-2. Neuron 47 845–857.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  108. Snyder, E. M., Philpot, B. D., Huber, K. M., Dong, X., Fallon, J. R., and Bear, M. F. (2001) Internalization of ionotropic glutamate receptors in response to mGluR activation. Nat. Neurosci. 4, 1079–1085.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  110. Rabow L. E., Russek S. J., and Farb D. H. (1995) From ion currents to genomic analysis recent advances in GABAA receptor research. Synapse 21, 189–274.

    Article  PubMed  CAS  Google Scholar 

  111. Sieghart W. and Sperk G. (2002) Subunit composition, distribution and function of GABA(A) receptor subtypes. Curr. Top Med. Chem. 2 795–816.

    Article  PubMed  CAS  Google Scholar 

  112. Luscher B. and Keller C. A. (2004) Regulation of GABAA receptor trafficking, channel activity, and functional plasticity of inhibitory synapses. Pharmacol. Ther. 102, 195–221.

    Article  PubMed  CAS  Google Scholar 

  113. Hanus C., Vannier C., and Triller A. (2004) Intracellular association of glycine receptor with gephyrin increases its plasma membrane accumulation rate. J. Neurosci. 24, 1119–1128.

    Article  PubMed  CAS  Google Scholar 

  114. Wang H., Bedford F. K., Brandon N. J., Moss S. J., and Olsen R. W. (1999) GABA(A)-receptor-associated protein links GABA(A) receptors and the cytoskeleton. Nature 397 69–72.

    Article  PubMed  CAS  Google Scholar 

  115. Wan, Q., Xiong, Z. G., Man, H. Y., et al. (1997) Recruitment of functional GABA(A) receptors to postsynaptic domains by insulin. Nature 388, 686–690.

    Article  PubMed  CAS  Google Scholar 

  116. Kumar S., Kralic J. E., O'Buckley T. K., Grobin A. C., and Morrow A. L. (2003) Chronic ethanol consumption enhances internalization of alphal subunit-containing GABAA receptors in cerebral cortex. J. Neurochem. 86, 700–708.

    Article  PubMed  CAS  Google Scholar 

  117. Kneussel M. (2002) Dynamic regulation of GABA(A) receptors at synaptic sites. Brain. Res. Rev. 39, 74–83.

    Article  PubMed  CAS  Google Scholar 

  118. Borden L. A., Czajkowski C., Chan C. Y., and Farb D. H. (1984) Benzodiazepine receptor synthesis and degradation by neurons in culture. Science 226, 857–860.

    Article  PubMed  CAS  Google Scholar 

  119. Kittler, J. T., Chen, G., Honing, S., et al. (2005) Phospho-dependent binding of the clathrin AP2 adaptor complex to GABAA receptors regulates the efficacy of inhibitory synaptic transmission. Proc. Natl. Acad. Sci. USA 102, 14,871–14,876.

    CAS  Google Scholar 

  120. Kittler, J. T., Rostaing, P., Schiavo, et al. (2001) The subcellular distribution of GABARAP and its ability to interact with NSF suggest a role for this protein in the intracellular transport of GABA(A) receptors. Mol. Cell Neurosci. 18, 13–25.

    Article  PubMed  CAS  Google Scholar 

  121. Herring, D., Huang, R., Singh, M., Robinson, L. C., Dillon, G. H., and Leidenheimer, N. J. (2003) Constitutive GABAA receptor endocytosis is dynamin-mediated and dependent on a difeucine AP2 adaptin-binding motif within the beta 2 subunit of the receptor. J. Biol. Chem. 278, 24,046–24,052.

    Article  CAS  Google Scholar 

  122. Connolly, C. N., Uren, J. M., Thomas, P., et al. (1999) Subcellular localization and endocytosis of homomeric gamma2 subunit splice variants of gamma-aminobutyric acid type A receptors. Mol. Cell Neurosci. 13, 259–271.

    Article  PubMed  CAS  Google Scholar 

  123. Barnes E. M. Jr. (2000) Intracellular trafficking of GABA(A) receptors. Life Sci. 66, 1063–1070.

    Article  PubMed  CAS  Google Scholar 

  124. Bedford, F. K., Kittler, J. T., Muller, E., et al. (2001) GABA(A) receptor cell surface number and subunit stability are regulated by the ubuquitin-like protein Plic-1. Nat. Neurosci. 4, 908–916.

    Article  PubMed  CAS  Google Scholar 

  125. Goto, H., Terunuma, M., Kanematsu, T., Misumi, Y., Moss, S. J., and Hirata, M. (2005) Direct interaction of N-ethylmaleimide-sensitive factor with GABA(A) receptor beta subunits. Mol. Cell Neurosci. 30, 197–206.

    Article  PubMed  CAS  Google Scholar 

  126. Kittler, J. T., Arancibia-Carcamo I. L., and Moss S. J. (2004) Association of GRIP1 with a GABA(A) receptor associated protein suggests a role for GRIP1 at inhibitory synapses. Biochem. Pharmacol. 68, 1649–1654.

    Article  PubMed  CAS  Google Scholar 

  127. Knuesel, I., Mastrocola, M., Zuellig, R. A., Bornhauser, B., Schaub, M. C., and Fritschy, J. M. (1999) Short communication: altered synaptic clustering of GABAA receptors in mice lacking dystrophin (mdx mice). Eur. J. Neurosci. 11 4457–4462.

    Article  PubMed  CAS  Google Scholar 

  128. Mishina, M., Takai, T., Imoto, K., et al. (1986) Molecular distinction between fetal and adult forms of muscle acetylcholine receptor. Nature 321, 406–411.

    Article  PubMed  CAS  Google Scholar 

  129. Gu Y. and Hall Z. W. (1988) Immunological evidence for a change in subunits of the acetylcholine receptor in developing and denervated rat muscle. Neuron 1, 117–125.

    Article  PubMed  CAS  Google Scholar 

  130. Missias A. C., Chu, G. C., Klocke, B. J., Sanes J. R., and Merlie J. P. (1996) Maturation of the acetylcholine receptor in skeletal muscle: regulation of the AChR gamma-to-epsilon switch. Dev. Biol. 179, 223–238.

    Article  PubMed  CAS  Google Scholar 

  131. Salpeter M. M. and Loring R. H. (1985) Nicotinic acetylcholine receptors in vertebrate muscle: properties, distribution and neural control. Prog. Neurobiol. 25, 297–325.

    Article  PubMed  CAS  Google Scholar 

  132. Bevan S. and Steinbach J. H. (1983) Denervation increases the degradation rate of acetylcholine receptors at end-plates in vivo and in vitro. J. Physiol. 336, 159–177.

    PubMed  CAS  Google Scholar 

  133. Stanley E. F. and Drachman D. B. (1983) Rapid degradation of “new” acetylcholine receptors at neuromuscular junctions. Science 222, 67–69.

    Article  PubMed  CAS  Google Scholar 

  134. Green D. P., Miledi R., Perez de la Mora M., and Vincent A. (1975) Acetylcholine receptors. Philos. Trans. R. Soc. Lond. B. Biol. Sci. 270, 551–559.

    PubMed  CAS  Google Scholar 

  135. Fambrough D. M. (1979) Control of acetylcholine receptors in skeletal muscle. Physiol. Rev. 59, 165–227.

    PubMed  CAS  Google Scholar 

  136. Akaaboune M., Culican S. M., Turney S. G. and Lichtman J. W. (1999) Rapid and reversible effects of activity on acetylcholine receptor density at the neuromuscular junction in vivo. Science 286, 503–507.

    Article  PubMed  CAS  Google Scholar 

  137. Gardner J. M. and Fambrough D. M. (1979) Acetylcholine receptor degradation, measured by density labeling: effects of cholinergic ligands and evidence against recycling. Cell 16, 661–674.

    Article  PubMed  CAS  Google Scholar 

  138. Bruneau E., Sutter D., Hume R. I., and Akaaboune M. (2005) Identification of nicotinic acetylcholine receptor recycling and its role in maintaining receptor density at the neuromuscular junction in vivo. J. Neurosci. 25, 9949–9959.

    Article  PubMed  CAS  Google Scholar 

  139. Akaaboune M., Grady R. M., Turney S., Sanes J. R., and Lichtman J. W. (2002) Neurotransmitter receptor dynamics studied in vivo by reversible photo-unbinding of fluorescent ligands. Neuron 34, 865–876.

    Article  PubMed  CAS  Google Scholar 

  140. Andreose J. S., Xu R., Lomo T., Salpeter M. M., and Fumagalli G. (1993) Degradation of two AChR populations at rat neuromuscular junctions: regulation in vivo by electrical stimulation. J. Neurosci. 13, 3433–3438.

    PubMed  CAS  Google Scholar 

  141. Caroni P., Rotzler S., Britt J. C., and Brenner H. R. (1993) Calcium influx and protein phosphorylation mediate the metabolic stabilization of synaptic acetylcholine receptors in muscle. J. Neurosci. 13, 1315–1325.

    PubMed  CAS  Google Scholar 

  142. Bruneau E. G., Macpherson P. C., Goldman D., Hume R. I., and Akaaboune M. (2005) The effect of agrin and laminin on acetylcholine receptor dynamics in vitro. Dev. Biol. 288, 248–258.

    Article  PubMed  CAS  Google Scholar 

  143. Shyng S. L. and Salpeter M. M. (1989) Degradation rate of acetylcholine receptors inserted into denervated vertebrate neuromuscular junctions. J. Cell. Biol. 108, 647–651.

    Article  PubMed  CAS  Google Scholar 

  144. Rotzler S., Schramek H., and Brenner H. R. (1991) Metabolic stabilization of endplate acetylcholine receptors regulated by Ca2+ influx associated with muscle activity. Nature 349, 337–339.

    Article  PubMed  CAS  Google Scholar 

  145. Rotzler S. and Brenner H. R. (1990) Metabolic stabilization of acetylcholine receptors in vertebrate neuromuscular junction by muscle activity. J. Cell Biol. 111, 655–661.

    Article  PubMed  CAS  Google Scholar 

  146. Bezakova G., Rabben I., Sefland I., Fumagalli G., and Lomo T. (2001) Neural agrin controls acetylcholine receptor stability in skeletal muscle fibers. Proc. Natl. Acad. Sci. USA 98, 9924–9929.

    Article  PubMed  CAS  Google Scholar 

  147. Adams, M. E., Kramarcy, N., Krall, S. P., et al. (2000) Absence of alpha-syntrophin leads to structurally aberrant neuromuscular synapses deficient in utrophin. J. Cell Biol. 150, 1385–1398.

    Article  PubMed  CAS  Google Scholar 

  148. Gervasio O. L. and Phillips W. D. (2005) Increased ratio of rapsyn to ACh receptor stabilizes postsynaptic receptors at the mouse neuromuscular synapse. J. Physiol. 562, 673–685.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Mohammed Akaaboune.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bruneau, E.G., Akaaboune, M. Running to stand still. Mol Neurobiol 34, 137–151 (2006). https://doi.org/10.1385/MN:34:2:137

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1385/MN:34:2:137

Index Entries

Navigation