at synapses that may also be capable of lateral diffusion. Despite the potential for receptor diffusion to synaptic membranes as a mechanism for targeting and the poten-tial significance of receptor migration between synapses, little research has focused on this issue.
A recent advance has been made by the use of single particle tracking to follow the lateral movement of glycine receptors expressed in the plasma membrane of trans-fected fibroblasts (Meier et al. 2001). The authors tracked the mobility of glycine recep-tors in cells coexpressing the glycine receptor (myc epitope-tagged) clustering molecule, gephyrin (GFP-tagged). The glycine receptors were tracked by labelling with a large (0.5 µm) bead coated with anti-myc antibodies. Receptors were found to alternate between periods of rapid lateral movement and relative immobility when associated with gephyrin-GFP clusters. This highlights the first important point, glycine receptors are not permanently restrained within gephyrin clusters. Secondly, the particles were found to be promiscuous, moving between gephyrin clusters. These findings are likely to represent an underestimate of receptor mobility due to the bind-ing of the bead to multiple receptors, pullbind-ing in different directions, and the require-ment for only a few receptor-gephyrin interactions to immobilize the bead. Despite these technical limitations, it will be important to perform similar studies on epitope-tagged receptors in neurons. Similar studies on the AMPA receptors have yielded the same pattern of diffusion, with receptors becoming immobilized at synaptic sites as neurons mature (Borgdorff and Choquet 2002), presumably due to their interaction with PSD-95 (Schnell et al. 2002).
Antonova, I., Arancio, O., Trillet, A-C., Wang, H-G., Zablow, L., Udo, H., et al. (2001) Rapid increase in clusters of presynaptic proteins at onset of long-lasting potentiation. Science, 294, 1547–50.
Banker, G. (2003) Pars, PI 3-kinase, and the establishment of neuronal polarity. Cell, 112, 4–5.
Barnes Jr, E. M. (1996) Use-dependent regulation of GABAAreceptors. Int. Rev. Neurobiol., 39, 53–76.
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, 435–49.
Bollan K., King, D., Robertson, L. A., Brown, K., Taylor, P. M., Moss, S. J., et al. (2003) GABA (A) receptor composition is determined by distinct assembly signals within alpha and beta subunits.
J. Biol. Chem., 278, 4747–55.
Borgdorff, A. J. and Choquet, D. (2002) Regulation of AMPA receptor lateral movements. Nature, 417, 649–53.
Boyd, G. W., Doward, A. I., Kirkness, E. F., Millar, N. S., and Connolly, C. N. (2003) Cell surface expression of 5-hydroxytryptamine type 3 receptors is controlled by an endoplasmic reticulum retention signal. J. Biol. Chem., 278, 27681–7.
Boyd, G. W., Low, P., Dunlop, J. I., Robertson, L. A., Vardy, A., Lambert, J. J., et al. (2002) Assembly and cell surface expression of homomeric and heteromeric 5-HT3 receptors: the role of oligomerization and chaperone proteins. Mol. Cell. Neurosci., 21, 38–50.
Buckley, K. M., Melikian, H. E., Provoda, C. J., and Waring, M. T. (2000) Regulation of neuronal function by protein trafficking: a role for the endosomal pathway. J. Physiol., 525.1, 11–19.
Burack, M. A., Silverman, M. A., and Banker, G. (2000) The role of selective transport in neuronal protein sorting. Neuron, 26, 465–72.
Connolly, C. N., Krishek, B. J., McDonald, B. J., Smart, T. G., and Moss, S. J. (1996) Assembly and cell surface expression of heteromeric and homomeric gamma-aminobutyric acid type A receptors.
J. Biol. Chem., 271, 89–96.
El-Husseini, A.E.-D., Craven, S. E., Brock, S. C., and Bredt, D. S. (2001) Polarized targeting of peripheral membrane proteins in neurons. J. Biol. Chem., 276, 44984–92.
Fukata, Y., Kimura, T., and Kaibuchi, K. (2002) Axon specification in hippocampal neurons. Neurosci.
Res., 43, 305–15.
Gardiol, A., Racca, C., and Triller, A. (1999) Dendritic and postsynaptic protein synthetic machinery.
J. Neurosci., 19, 168–79.
Girault, J. A. and Peles, E. (2002) Development of nodes of Ranvier. Curr. Opin. Neurobiol., 12, 476–85.
Greger, I. H., Khatri, L., and Ziff, E. B. (2002) RNA editing at arg607 controls AMPA receptor exit from the endoplasmic reticulum. Neuron, 34, 759–72.
Grosshans, D. R., Clayton, D. A., Coultrap, S. J., and Browning, M. D. (2001) LTP leads to rapid surface expression of NMDA but not AMPA receptors in adult rat CA1. Nat. Neurosci., 5, 27–33.
Hirbec, H., Francis, J. C., Lauri, S. E., Braithwaite, S. P., Coussen, F., Mulle, C., et al. (2003) Rapid and differential regulation of AMPA and kainate receptors at hippocampal mossy fibre synapses by PICK1 and GRIP. Neuron, 37, 625–38.
Ikonen, E. (2001) Roles of lipid rafts in membrane transport. Curr. Opin. Cell Biol., 13, 470–77.
Imamura, F., Maeda, S., Doi, T., and Fujiyoshi, Y. (2002) Ligand binding of the second PDZ domain regulates clustering of PSD-95 with the Kv1.4 potassium channel. J. Biol. Chem., 277,
3640–6.
Jareb, M. and Banker, G. (1998) The polarized sorting of membrane proteins expressed in cultured hippocampal neurons using viral vectors. Neuron, 20, 855–67.
Job, C. and Eberwine, J. (2001) Localization and translation of mRNA in dendrites and axons.
Nat. Rev. Neurosci., 2, 889–98.
Kaether, C., Skehel, P., and Dotti, C. G. (2000) Axonal membrane proteins are transported in distinct carriers: a two-colour video microscopy study in cultured hippocampal neurons. Mol. Biol. Cell, 11, 1213–24.
Kamiguchi, H. and Lemmon, V. (1998) A neuronal form of the cell adhesion molecule L1 contains a tyrosine-based signal required for sorting to the axonal growth cone. J. Neurosci., 18, 3749–56.
Kittler, J. T. and Moss, S. J. (2001) Neurotransmitter receptor trafficking and the regulation of synaptic strength. Traffic, 2, 437–48.
Kneussel, M. (2002) Dynamic regulation of GAB(A) receptors at synaptic sites. Brain Res. Brain Res.
Dev., 39, 74–83.
Ma, D., Zerangue, N., Lin, Y.-F., Collins, A., Yu, M., Jan, Y. N., et al. (2001) Role of ER export signals in controlling surface potassium channel numbers. Science, 291, 316–19.
Malinow, R. and Malenka, R. C. (2002) AMPA receptor trafficking and synaptic plasticity. Annu. Rev.
Neurosci., 25, 103–26.
Meddows, E., Le Bourdelles, B., Grimwood, S., Wafford, K., Sandhu, S., Whiting, P., et al. (2001) Identification of molecular determinants that are important in the assembly of N-methyl-D-aspartate receptors. J. Biol. Chem., 276, 18795–803.
Meier, J., Vannier, C., Serge, A., Triller, A., and Choquet, D. (2001) Fast and reversible trapping of surface glycine receptors by gephyrin. Nat. Neurosci., 4, 253–60.
Passafaro, M., Piech, V., and Sheng, M. (2001) Subunit-specific temporal and spatial patterns of AMPA receptor exocytosis in hippocampal neurons. Nat. Neurosci., 4, 917–26.
Prange, O. and Murphy, T. H. (2001) Modular transport of postsynaptic density-95 clusters and association with stable spine precursors during early development of cortical neurons. J.
Neurosci., 21, 9325–33.
Rasband, M. N. and Trimmer, J. S. (2001) Developmental clustering of ion channels at and near the node of Ranvier. Dev. Biol., 236, 5–16.
Rivera, J. F., Ahmed, S., Quick, M. W., Liman, E. R., and Arnold, D. B. (2003) An evolutionarily conserved dileucine motif in Shal K(+) channels mediates dendritic targeting. Nat. Neurosci., 6, 243–50.
Roche, K. W., Standley, S., McCallum, J., Ly, C. D., Ehlers, M. D., and Wenthold, R. J. (2001) Molecular determinants of NMDA receptor internalization. Nat. Neurosci., 4, 794–802.
Sampo, B., Kaech, S., Kunz, S., and Banker, G. (2003) Two distinct mechanisms target membrane proteins to the axonal surface. Neuron, 37, 611–24.
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 number. Proc. Natl.
Acad. Sci., USA, 99, 13902–7.
Schwappach, B., Zerangue, N., Jan, Y. N., and Jan, L. Y. (2000) Molecular basis for K(ATP) assembly:
transmembrane interactions mediate association of a K+channel with an ABC transporter.
Neuron, 26, 155–67.
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, 3063–72.
Sheng, M., Lee, S. H. (2001) AMPA receptor trafficking and the control of synaptic transmission.
Cell, 105, 825–8.
Silverman, M. A., Kaech, S., Jareb, M., Burack, M. A., Vogt, L., Sonderegger, P., et al. (2001) Sorting and directed transport of membrane proteins during development of hippocampal neurons in culture. Proc. Natl. Acad. Sci. USA, 98, 7051–7.
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, 1079–85.
Stockklausner, C. and Klocker, N. (2003) Surface expression of inward rectifier potassium channels is controlled by selective Golgi export. J. Biol. Chem. [epub ahead of print].
Stowell, J. N. and Craig, A. M. (1999) Axon/dendrite targeting of metabotropic glutamate receptors by their cytoplasmic carboxy-terminal domains. Neuron, 22, 525–36.
Takeda, T., Yamazaki, H., and Farquhar, M. G. (2003) Identification of an Apical Sorting Determinant in the Cytoplasmic Tail of Megalin. Am. J. Physiol. Cell Physiol. [epub ahead of print].
Tang, B. L. (2001) Protein trafficking mechanisms associated with neurite outgrowth and polarized sorting in neurons. J. Neurochem., 79, 923–30.
Tsui-Pierchala, B. A., Encinas, M., Milbrandt, J., and Johnson Jr, E. M. (2002) Lipid rafts in neuronal signaling and function. Trends Neurosci., 25, 412–7.
Votsmeier, C. and Gallwitz, D. (2001) An acidic sequence of a putative yeast Golgi membrane protein binds COPII and facilitates ER export. EMBO J., 20, 6742–50.
Wang, J., Liu, S., Haditsch, U., Tu, W., Cochrane, K., Ahmadian, G., et al. (2003) Interaction of calcineurin and type-A GABA receptor gamma 2 subunits produces long-term depression at CA1 inhibitory synapses. J. Neurosci., 23, 826–36.
Winckler, B., Forscher, P., and Mellman, I. (1999) A diffusion barrier maintains distribution of membrane proteins in polarized neurons. Nature, 397, 698–701.
Zerangue, N., Malan, M. J., Fried, S. R., Dazin, P. F., Jan, Y. N., Jan, L. Y., et al. (2001) Analysis of endoplasmic reticulum trafficking signals by combinatorial screening in mammalian cells.
Proc. Natl. Acad. Sci. USA, 98, 2431–6.
Zhai, R., Vardinon-Friedman, H., Cases-Langhoff, C., and Becker, B. (2001) Assembling the presynaptic active zone: Characterization of an active zone precursor vesicle. Neuron, 29, 131–43.
Ziv, N. E. and Garner, C. C. (2001) Principles of glutamatergic synapse formation: Seeing the forest for the trees. Curr. Opin. Neurobiol., 11, 536–43.