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The Journal of Neuroscience, June 23, 2004, 24(25):5816-5826; doi:10.1523/JNEUROSCI.1184-04.2004

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Cellular/Molecular
The GDP-GTP Exchange Factor Collybistin: An Essential Determinant of Neuronal Gephyrin Clustering

Kirsten Harvey,¹ Ian C. Duguid,^2 * Melissa J. Alldred,^3 * Sarah E. Beatty,⁴ Hamish Ward,⁴ Nicholas H. Keep,⁵ Sue E. Lingenfelter,³ Brian R. Pearce,¹ Johan Lundgren,⁶ Michael J. Owen,⁷ Trevor G. Smart,² Bernhard Lüscher,³ Mark I. Rees,^4,8 and Robert J. Harvey¹

¹Department of Pharmacology, The School of Pharmacy, London WC1N 1AX, United Kingdom, ²Department of Pharmacology, University College London, London WC1E 6BT, United Kingdom, ³Department of Biology and Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, Pennsylvania 16802, ⁴Department of Molecular Medicine, Faculty of Medical and Health Sciences, University of Auckland, Private bag 92019, Auckland, New Zealand, ⁵School of Crystallography, Birkbeck, University of London, London WC1E 7HX, United Kingdom, ⁶Department of Pediatrics, University Hospital, SE-221 85 Lund, Sweden, ⁷Psychological Medicine, University of Wales College of Medicine, Cardiff CF14 4XN, United Kingdom, and ⁸Swansea Clinical School, University of Wales, Swansea SA2 8PP, United Kingdom

Glycine receptors (GlyRs) and specific subtypes of GABA_A receptors are clustered at synapses by the multidomain protein gephyrin, which in turn is translocated to the cell membrane by the GDP-GTP exchange factor collybistin. We report the characterization of several new variants of collybistin, which are created by alternative splicing of exons encoding an N-terminal src homology 3 (SH3) domain and three alternate C termini (CB1, CB2, and CB3). The presence of the SH3 domain negatively regulates the ability of collybistin to translocate gephyrin to submembrane microaggregates in transfected mammalian cells. Because the majority of native collybistin isoforms appear to harbor the SH3 domain, this suggests that collybistin activity may be regulated by protein-protein interactions at the SH3 domain. We localized the binding sites for collybistin and the GlyR subunit to the C-terminal MoeA homology domain of gephyrin and show that multimerization of this domain is required for collybistin-gephyrin and GlyR-gephyrin interactions. We also demonstrate that gephyrin clustering in recombinant systems and cultured neurons requires both collybistin-gephyrin interactions and an intact collybistin pleckstrin homology domain. The vital importance of collybistin for inhibitory synaptogenesis is underlined by the discovery of a mutation (G55A) in exon 2 of the human collybistin gene (ARHGEF9) in a patient with clinical symptoms of both hyperekplexia and epilepsy. The clinical manifestation of this collybistin missense mutation may result, at least in part, from mislocalization of gephyrin and a major GABA_A receptor subtype.

Key words: dendritic transport; epilepsy; GABA_A receptor; glycine receptor; hyperekplexia; trafficking

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Received Nov 25, 2003; revised May 12, 2004; accepted May 13, 2004.

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