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J. Biol. Chem., Vol. 281, Issue 40, 30046-30056, October 6, 2006

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Regulation of Gephyrin Assembly and Glycine Receptor Synaptic Stability^*

From the INSERM U789, the Laboratoire de Biologie Cellulaire de la Synapse, Ecole Normale Supérieure, F-75005, Paris, France

Gephyrin is required for the formation of clusters of the glycine receptor (GlyR) in the neuronal postsynaptic membrane. It can make trimers and dimers through its N- and C-terminal G and E domains, respectively. Gephyrin oligomerization could thus create a submembrane lattice providing GlyR-binding sites. We investigated the relationships between the stability of cell surface GlyR and the ability of gephyrin splice variants to form oligomers. Using truncated and full-length gephyrins we found that the 13-amino acid sequence (cassette 5) prevents G domain trimerization. Moreover, E domain dimerization is inhibited by the gephyrin central L domain. All of the gephyrin variants bind GlyR subunit cytoplasmic loop with high affinity regardless of their cassette composition. Coexpression experiments in COS-7 cells demonstrated that GlyR bound to gephyrin harboring cassette 5 cannot be stabilized at the cell surface. This gephyrin variant was found to deplete synapses from both GlyR and gephyrin in transfected neurons. These data suggest that the relative expression level of cellular variants influence the overall oligomerization pattern of gephyrin and thus the turnover of synaptic GlyR.

Received for publication, March 7, 2006 , and in revised form, June 14, 2006.

^* This work was supported by grants from the Association Française contre les Myopathies and from the Institut de Recherche sur la Moelle Epinière. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental text and figures.

¹ Supported by the Institut National de la Santé et de la Recherche Médicale.

² To whom correspondence should be addressed: Laboratoire de Biologie Cellulaire de la Synapse Normale et Pathologique, INSERM U789, Ecole Normale Supérieure, 46 rue d'Ulm, 75005 Paris, France. Tel.: 33-1-44-32-35-36; Fax: 33-1-44-32-36-54; E-mail: vannier{at}wotan.ens.fr.

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