Several posttranslational modifications act in concert to regulate gephyrin scaffolding and GABAergic transmission

Open access
Date
2016Type
- Journal Article
Citations
Cited 45 times in
Web of Science
Cited 43 times in
Scopus
ETH Bibliography
yes
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Abstract
GABAA receptors (GABAARs) mediate the majority of fast inhibitory neurotransmission in the brain via synergistic association with the postsynaptic scaffolding protein gephyrin and its interaction partners. However, unlike their counterparts at glutamatergic synapses, gephyrin and its binding partners lack canonical protein interaction motifs; hence, the molecular basis for gephyrin scaffolding has remained unclear. In this study, we identify and characterize two new posttranslational modifications of gephyrin, SUMOylation and acetylation. We demonstrate that crosstalk between SUMOylation, acetylation and phosphorylation pathways regulates gephyrin scaffolding. Pharmacological intervention of SUMO pathway or transgenic expression of SUMOylation-deficient gephyrin variants rescued gephyrin clustering in CA1 or neocortical neurons of Gabra2-null mice, which otherwise lack gephyrin clusters, indicating that gephyrin SUMO modification is an essential determinant for scaffolding at GABAergic synapses. Together, our results demonstrate that concerted modifications on a protein scaffold by evolutionarily conserved yet functionally diverse signalling pathways facilitate GABAergic transmission. Show more
Permanent link
https://doi.org/10.3929/ethz-b-000122567Publication status
publishedExternal links
Journal / series
Nature CommunicationsVolume
Pages / Article No.
Publisher
Nature Publishing GroupOrganisational unit
03742 - Zeilhofer, Hanns U. / Zeilhofer, Hanns U.
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Show all metadata
Citations
Cited 45 times in
Web of Science
Cited 43 times in
Scopus
ETH Bibliography
yes
Altmetrics