Gephyrin-mediated γ-Aminobutyric Acid Type A and Glycine Receptor Clustering Relies on a Common Binding Site

• DOI: 10.1074/jbc.m111.303412
• Publication Date: 2011-10-18T04:50:14Z
• Authors: Hans-Michael Maric; Jayanta Mukherjee; Verena Tretter; Stephen J. Moss; Hermann Schindelin
• Keywords: Gephyrin

Gephyrin is the major protein determinant for clustering of inhibitory neurotransmitter receptors. Earlier analyses revealed that gephyrin tightly binds to residues 398-410 glycine receptor β subunit (GlyR β) and, as demonstrated only recently, also interacts with GABA(A) receptors (GABA(A)Rs) containing α1, α2, and α3 subunits. Here, we dissect molecular basis underlying interactions between GABA(A)Rs these α-subunits compare them crystal structure gephyrin-GlyR complex. Biophysical biochemical assays that, in contrast its tight interaction GlyR β, loosely GABA(A)R whereas it has an intermediate affinity α1 Despite wide variation affinities low overall sequence homology among identified subunits, competition confirmed receptor-gephyrin be a mutually exclusive process. Selected point mutants critically weaken complex formation abolished interactions. Additionally, common binding motif two conserved aromatic are central binding. Consistent data, mutations corresponding within cytoplasmic domain α2 subunit-containing attenuated at postsynaptic sites hippocampal neurons. Taken together, our experiments provide key insights regarding similarities differences compared GlyRs hence, accumulation sites.