The GDP-GTP exchange factor collybistin: an essential determinant of neuronal gephyrin clustering

Harvey, K., Duguid, I.C., Alldred, M.J., Beatty, S.E., Ward, H., Keep, N.H., Lingenfelter, S.E., Pearce, B.R., Lundgren, J., Owen, M.J., Smart, T.G., Luscher, B., Rees, M.I. and Harvey, R.J. (2004) The GDP-GTP exchange factor collybistin: an essential determinant of neuronal gephyrin clustering. Journal of Neuroscience, 24 (25). pp. 5816-5826. 10.1523/JNEUROSCI.1184-04.2004.

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DOI: 10.1523/JNEUROSCI.1184-04.2004

Abstract

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 beta 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.

Item Type:Article
Additional Information:The published article is available from the Society of Neuroscience. Full text can be accessed electronically at the School of Pharmacy Library.
Departments, units and centres:Department of Pharmacology > Department of Pharmacology
ID Code:769
Journal or Publication Title:Journal of Neuroscience
Deposited By:Library Staff
Deposited On:15 May 2007
Last Modified:10 Nov 2011 09:42

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