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

Himanish Ghosh, Luca Auguadri, Sereina Battaglia, Zahra Simone Thirouin, Khaled Zemoura, Simon Messner, Mario A. Acuña, Hendrik Wildner, Gonzalo E. Yévenes, Andrea Dieter, Hiroshi Kawasaki, Michael O. Hottiger, Hanns Ulrich Zeilhofer, Jean-Marc Fritschy and Shiva K. Tyagarajan ()
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Himanish Ghosh: Institute of Pharmacology and Toxicology, University of Zurich
Luca Auguadri: Institute of Pharmacology and Toxicology, University of Zurich
Sereina Battaglia: Institute of Pharmacology and Toxicology, University of Zurich
Zahra Simone Thirouin: Institute of Pharmacology and Toxicology, University of Zurich
Khaled Zemoura: Institute of Pharmacology and Toxicology, University of Zurich
Simon Messner: University of Zurich
Mario A. Acuña: Institute of Pharmacology and Toxicology, University of Zurich
Hendrik Wildner: Institute of Pharmacology and Toxicology, University of Zurich
Gonzalo E. Yévenes: Institute of Pharmacology and Toxicology, University of Zurich
Andrea Dieter: Institute of Pharmacology and Toxicology, University of Zurich
Hiroshi Kawasaki: Graduate School of Medicine, The University of Tokyo
Michael O. Hottiger: University of Zurich
Hanns Ulrich Zeilhofer: Institute of Pharmacology and Toxicology, University of Zurich
Jean-Marc Fritschy: Institute of Pharmacology and Toxicology, University of Zurich
Shiva K. Tyagarajan: Institute of Pharmacology and Toxicology, University of Zurich

Nature Communications, 2016, vol. 7, issue 1, 1-16

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms13365

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