QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, November 9, 2005, 25(45):10469-10478; doi:10.1523/JNEUROSCI.2267-05.2005

This Article Full Text Full Text (PDF) Supplemental data Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (37) Citing Articles via Google Scholar Google Scholar Articles by Jacob, T. C. Articles by Moss, S. J. Search for Related Content PubMed PubMed Citation Articles by Jacob, T. C. Articles by Moss, S. J.

 Previous Article  |  Next Article 

Cellular/Molecular
Gephyrin Regulates the Cell Surface Dynamics of Synaptic GABA_A Receptors

Tija C. Jacob,^1 * Yury D. Bogdanov,^2 * Christopher Magnus,² Richard S. Saliba,² Josef T. Kittler,¹ Philip G. Haydon,¹ and Stephen J. Moss^1,2

¹Department of Pharmacology, University College London, London WC1E 6BT, United Kingdom, and ²Department of Neuroscience, University of Pennsylvania, Philadelphia, Pennsylvania 19104

The efficacy of fast synaptic inhibition is critically dependent on the accumulation of GABA_A receptors at inhibitory synapses, a process that remains poorly understood. Here, we examined the dynamics of cell surface GABA_A receptors using receptor subunits modified with N-terminal extracellular ecliptic pHluorin reporters. In hippocampal neurons, GABA_A receptors incorporating pHluorin-tagged subunits were found to be clustered at synaptic sites and also expressed as diffuse extrasynaptic staining. By combining FRAP (fluorescence recovery after photobleaching) measurements with live imaging of FM4-64-labeled active presynaptic terminals, it was evident that clustered synaptic receptors exhibit significantly lower rates of mobility at the cell surface compared with their extrasynaptic counterparts. To examine the basis of this confinement, we used RNAi to inhibit the expression of gephyrin, a protein shown to regulate the accumulation of GABA_A receptors at synaptic sites. However, whether gephyrin acts to control the actual formation of receptor clusters, their stability, or is simply a global regulator of receptor cell surface number remains unknown. Inhibiting gephyrin expression did not modify the total number of GABA_A receptors expressed on the neuronal cell surface but significantly decreased the number of receptor clusters. Live imaging revealed that clusters that formed in the absence of gephyrin were significantly more mobile compared with those in control neurons. Together, our results demonstrate that synaptic GABA_A receptors have lower levels of lateral mobility compared with their extrasynaptic counterparts, and suggest a specific role for gephyrin in reducing the diffusion of GABA_A receptors, facilitating their accumulation at inhibitory synapses.

Key words: imaging; GABA; GABA_A receptor; GABA synaptogenesis; GABA_A receptor trafficking; GABAergic modulation

---

Received June 3, 2005; revised August 13, 2005; accepted October 5, 2005.

This article has been cited by other articles:

				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 J. Biol. Chem., July 4, 2008; 283(27): 18538 - 18544. [Abstract] [Full Text] [PDF]

				E. C. Sarro, V. C. Kotak, D. H. Sanes, and C. Aoki Hearing Loss Alters the Subcellular Distribution of Presynaptic GAD and Postsynaptic GABAA Receptors in the Auditory Cortex Cereb Cortex, April 9, 2008; (2008) bhn044v1. [Abstract] [Full Text] [PDF]

				V. Tretter, T. C. Jacob, J. Mukherjee, J.-M. Fritschy, M. N. Pangalos, and S. J. Moss The Clustering of GABAA Receptor Subtypes at Inhibitory Synapses is Facilitated via the Direct Binding of Receptor {alpha}2 Subunits to Gephyrin J. Neurosci., February 6, 2008; 28(6): 1356 - 1365. [Abstract] [Full Text] [PDF]

				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 J. Neurosci., November 28, 2007; 27(48): 13341 - 13351. [Abstract] [Full Text] [PDF]

				A. M. Pooler and R. A. J. McIlhinney Lateral Diffusion of the GABAB Receptor Is Regulated by the GABAB2 C Terminus J. Biol. Chem., August 31, 2007; 282(35): 25349 - 25356. [Abstract] [Full Text] [PDF]

				C. Bouzigues, M. Morel, A. Triller, and M. Dahan Asymmetric redistribution of GABA receptors during GABA gradient sensing by nerve growth cones analyzed by single quantum dot imaging PNAS, July 3, 2007; 104(27): 11251 - 11256. [Abstract] [Full Text] [PDF]

				M.-V. Ehrensperger, C. Hanus, C. Vannier, A. Triller, and M. Dahan Multiple Association States between Glycine Receptors and Gephyrin Identified by SPT Analysis Biophys. J., May 15, 2007; 92(10): 3706 - 3718. [Abstract] [Full Text] [PDF]

				B. Lardi-Studler and J.-M. Fritschy Matching of Pre- and Postsynaptic Specializations during Synaptogenesis Neuroscientist, April 1, 2007; 13(2): 115 - 126. [Abstract] [PDF]

				T. Saiyed, I. Paarmann, B. Schmitt, S. Haeger, M. Sola, G. Schmalzing, W. Weissenhorn, and H. Betz Molecular Basis of Gephyrin Clustering at Inhibitory Synapses: ROLE OF G- AND E-DOMAIN INTERACTIONS J. Biol. Chem., February 23, 2007; 282(8): 5625 - 5632. [Abstract] [Full Text] [PDF]

				C. Bouzigues and M. Dahan Transient Directed Motions of GABAA Receptors in Growth Cones Detected by a Speed Correlation Index Biophys. J., January 15, 2007; 92(2): 654 - 660. [Abstract] [Full Text] [PDF]

				C. Charrier, M.-V. Ehrensperger, M. Dahan, S. Levi, and A. Triller Cytoskeleton Regulation of Glycine Receptor Number at Synapses and Diffusion in the Plasma Membrane. J. Neurosci., August 15, 2006; 26(33): 8502 - 8511. [Abstract] [Full Text] [PDF]

				L. Cognet, L. Groc, B. Lounis, and D. Choquet Multiple Routes for Glutamate Receptor Trafficking: Surface Diffusion and Membrane Traffic Cooperate to Bring Receptors to Synapses Sci. Signal., March 21, 2006; 2006(327): pe13 - pe13. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help