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.
Highlights
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
Western blot (WB) analysis showed higher migrating SUMOylated bands of gephyrin, suggesting that it could be a novel substrate for SUMO1 and SUMO2 (Fig. 1a)
Gephyrin and its main interaction partners lack such an interaction domain, indicating that protein scaffolds at inhibitory synapses rely on distinct regulation mechanisms
Summary
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. Unlike their counterparts at glutamatergic synapses, gephyrin and its binding partners lack canonical protein interaction motifs; the molecular basis for gephyrin scaffolding has remained unclear. We demonstrate that crosstalk between SUMOylation, acetylation and phosphorylation pathways regulates gephyrin scaffolding. Cross-talk between different PTMs, such as phosphorylation-dependent SUMOylation or competition between SUMOylation and acetylation of the same lysine residues on specific substrates, expands this repertoire even further and allows rapid switches in protein functional states under the influence of a variety of signalling cascades[6,7,8,9,10]. The phosphorylation status of residues S268 and S270 on gephyrin influences gephyrin scaffolding properties and thereby directly impinge on GABAAR synaptic function[17,18]
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