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

K Harvey; I C Duguid; M J Alldred; S E Beatty; H Ward; N H Keep; S E Lingenfelter; B R Pearce; J Lundgren; M J Owen; T G Smart; B Luscher; M I Rees; Robert J Harvey

doi:10.1523/JNEUROSCI.1184-04.2004

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

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

K Harvey, I C Duguid, M J Alldred, S E Beatty, H Ward, N H Keep, S E Lingenfelter, B R Pearce, J Lundgren, M J Owen, …

Journal of Neuroscience, Vol.24(25), pp.5816-5826

2004

DOI: https://doi.org/10.1523/JNEUROSCI.1184-04.2004

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Abstract

Medical and Health Sciences

Psychology and Cognitive Sciences

dendritic transport

epilepsy

GABAA receptor

glycine receptor

hyperekplexia

trafficking

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 β 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.

Details

Title: The GDP-GTP Exchange Factor Collybistin: An Essential Determinant of Neuronal Gephyrin Clustering
Authors: K Harvey (Author) - University College London, United Kingdom
I C Duguid (Author) - University College London, United Kingdom
M J Alldred (Author) - Pennsylvania State University, United States
S E Beatty (Author) - University of Auckland, New Zealand
H Ward (Author) - University of Auckland, New Zealand
N H Keep (Author) - University of London, United Kingdom
S E Lingenfelter (Author) - Pennsylvania State University, United States
B R Pearce (Author) - University College London, United Kingdom
J Lundgren (Author) - University Hospital, Sweden
M J Owen (Author) - University of Wales, United Kingdom
T G Smart (Author) - University College London, United Kingdom
B Luscher (Author) - Pennsylvania State University, United States
M I Rees (Author) - University of Auckland, New Zealand
Robert J Harvey (Author) - University College London, United Kingdom
Publication details: Journal of Neuroscience, Vol.24(25), pp.5816-5826
Publisher: Society for Neuroscience (SFN)
Date published: 2004
DOI: 10.1523/JNEUROSCI.1184-04.2004
ISSN: 0270-6474
Copyright note: Copyright © 2004 The Authors. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
Organisation Unit: School of Health; University of the Sunshine Coast, Queensland; School of Health and Sport Sciences - Legacy; Centre for Bioinnovation; School of Health and Behavioural Sciences - Legacy
Language: English
Record Identifier: 99450360302621
Output Type: Journal article

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Web Of Science research areas: Neurosciences

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