Journal article
Complex role of collybistin and gephyrin in GABAA receptor clustering
Journal of Biological Chemistry, Vol.285(38), pp.29623-29631
2010
Abstract
Gephyrin and collybistin are key components of GABAA receptor (GABAAR) clustering. Nonetheless, resolving the molecular interactions between the plethora of GABAAR subunits and these clustering proteins is a significant challenge. We report a direct interaction of GABAAR α2 and α3 subunit intracellular M3-M4 domain (but not α1, α4, α5, α6, β1-3, or γ1-3) with gephyrin. Curiously, GABAAR α2, but not α3, binds to both gephyrin and collybistin using overlapping sites. The reciprocal binding sites on gephyrin for collybistin and GABAAR α2 also overlap at the start of the gephyrin E domain. This suggests that although GABAAR α3 interacts with gephyrin, GABAAR α2, collybistin, and gephyrin form a trimeric complex. In support of this proposal, tri-hybrid interactions between GABAAR α2 and collybistin or GABA AR α2 and gephyrin are strengthened in the presence of gephyrin or collybistin, respectively. Collybistin and gephyrin also compete for binding to GABAAR α2 in co-immunoprecipitation experiments and co-localize in transfected cells in both intracellular and submembrane aggregates. Interestingly, GABAAR α2 is capable of "activating " collybistin isoforms harboring the regulatory SH3 domain, enabling targeting of gephyrin to the submembrane aggregates. The GABAAR α2-collybistin interaction was disrupted by a pathogenic mutation in the collybistin SH3 domain (p.G55A) that causes X-linked intellectual disability and seizures by disrupting GABAAR and gephyrin clustering. Because immunohistochemistry in retina revealed a preferential co-localization of collybistin with α2 subunit containing GABAARs, but not GlyRs or other GABAAR subtypes, we propose that the collybistin-gephyrin complex has an intimate role in the clustering of GABAARs containing the α2 subunit. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.
Details
- Title
- Complex role of collybistin and gephyrin in GABAA receptor clustering
- Authors
- L Saiepour (Author) - University of London, United KingdomC Fuchs (Author) - University of London, United KingdomA Patrizi (Author) - University of Turin, ItalyM Sassoè-Pognetto (Author) - University of Turin, ItalyRobert J Harvey (Author) - University of London, United KingdomK Harvey (Author) - University of London, United Kingdom
- Publication details
- Journal of Biological Chemistry, Vol.285(38), pp.29623-29631
- Publisher
- American Society for Biochemistry and Molecular Biology, Inc.
- Date published
- 2010
- DOI
- 10.1074/jbc.M110.121368
- ISSN
- 0021-9258
- Copyright note
- Copyright © 2010 by the American Society for Biochemistry and Molecular Biology, Inc. The published version is reproduced here in accordance with the publisher's copyright policy
- 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
- 99451021102621
- Output Type
- Journal article
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