Molecular basis of the alternative recruitment of GABA(A) versus glycine receptors through gephyrin

TY - JOUR

T1 - Molecular basis of the alternative recruitment of GABA(A) versus glycine receptors through gephyrin

AU - Maric, Hans-Michael

AU - Kasaragod, Vikram Babu

AU - Hausrat, Torben Johann

AU - Kneussel, Matthias

AU - Tretter, Verena

AU - Strømgaard, Kristian

AU - Schindelin, Hermann

PY - 2014/12/22

Y1 - 2014/12/22

N2 - γ-Aminobutyric acid type A and glycine receptors (GABA(A)Rs, GlyRs) are the major inhibitory neurotransmitter receptors and contribute to many synaptic functions, dysfunctions and human diseases. GABA(A)Rs are important drug targets regulated by direct interactions with the scaffolding protein gephyrin. Here we deduce the molecular basis of this interaction by chemical, biophysical and structural studies of the gephyrin-GABA(A)R α3 complex, revealing that the N-terminal region of the α3 peptide occupies the same binding site as the GlyR β subunit, whereas the C-terminal moiety, which is conserved among all synaptic GABA(A)R α subunits, engages in unique interactions. Thermodynamic dissections of the gephyrin-receptor interactions identify two residues as primary determinants for gephyrin's subunit preference. This first structural evidence for the gephyrin-mediated synaptic accumulation of GABA(A)Rs offers a framework for future investigations into the regulation of inhibitory synaptic strength and for the development of mechanistically and therapeutically relevant compounds targeting the gephyrin-GABA(A)R interaction.

AB - γ-Aminobutyric acid type A and glycine receptors (GABA(A)Rs, GlyRs) are the major inhibitory neurotransmitter receptors and contribute to many synaptic functions, dysfunctions and human diseases. GABA(A)Rs are important drug targets regulated by direct interactions with the scaffolding protein gephyrin. Here we deduce the molecular basis of this interaction by chemical, biophysical and structural studies of the gephyrin-GABA(A)R α3 complex, revealing that the N-terminal region of the α3 peptide occupies the same binding site as the GlyR β subunit, whereas the C-terminal moiety, which is conserved among all synaptic GABA(A)R α subunits, engages in unique interactions. Thermodynamic dissections of the gephyrin-receptor interactions identify two residues as primary determinants for gephyrin's subunit preference. This first structural evidence for the gephyrin-mediated synaptic accumulation of GABA(A)Rs offers a framework for future investigations into the regulation of inhibitory synaptic strength and for the development of mechanistically and therapeutically relevant compounds targeting the gephyrin-GABA(A)R interaction.

U2 - 10.1038/ncomms6767

DO - 10.1038/ncomms6767

M3 - Journal article

C2 - 25531214

SN - 2041-1723

VL - 5

SP - 1

EP - 11

JO - Nature Communications

JF - Nature Communications

M1 - 5767

ER -