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

Harvey, Kirsten, Duguid, Ian C, Alldred, Melissa J., Beatty, Sarah E., Ward, Hamish, Keep, Nicholas H., Lingenfelter, Sue E., Pearce, Brian R., Lundgren, Johan, Owen, Michael John, Smart, Trevor G., Lüscher, Bernhard, Rees, Mark I. and Harvey, Robert 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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Abstract

Glycine receptors (GlyRs) and specific subtypes of GABAA 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 GABAA receptor subtype.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Neuroscience and Mental Health Research Institute (NMHRI)
Uncontrolled Keywords: Dendritic transport ; Epilepsy ; GABAA receptor ; Glycine receptor ; Hyperekplexia ; Trafficking
Additional Information: “Copyright of all material published in The Journal of Neuroscience remains with the authors. The authors grant the Society for Neuroscience an exclusive license to publish their work for the first 6 months. After 6 months the work becomes available to the public to copy, distribute, or display under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported license.(http://creativecommons.org/licenses/)” See: http://www.jneurosci.org/site/misc/ifa_policies.xhtml
Publisher: Society for Neuroscience
ISSN: 02706474
Last Modified: 04 Jun 2017 01:35
URI: http://orca.cf.ac.uk/id/eprint/629

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