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Molecular basis of the alternative recruitment of GABAA versus glycine receptors through gephyrin

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  • Hans Michael Maric

    (Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg
    University of Copenhagen)

  • Vikram Babu Kasaragod

    (Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg)

  • Torben Johann Hausrat

    (Center for Molecular Neurobiology, ZMNH, University Medical Center Hamburg-Eppendorf)

  • Matthias Kneussel

    (Center for Molecular Neurobiology, ZMNH, University Medical Center Hamburg-Eppendorf)

  • Verena Tretter

    (Medical University Vienna)

  • Kristian Strømgaard

    (University of Copenhagen)

  • Hermann Schindelin

    (Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg)

Abstract

γ-Aminobutyric acid type A and glycine receptors (GABAARs, GlyRs) are the major inhibitory neurotransmitter receptors and contribute to many synaptic functions, dysfunctions and human diseases. GABAARs 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–GABAAR 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 GABAAR 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 GABAARs 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–GABAAR interaction.

Suggested Citation

  • Hans Michael Maric & Vikram Babu Kasaragod & Torben Johann Hausrat & Matthias Kneussel & Verena Tretter & Kristian Strømgaard & Hermann Schindelin, 2014. "Molecular basis of the alternative recruitment of GABAA versus glycine receptors through gephyrin," Nature Communications, Nature, vol. 5(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms6767
    DOI: 10.1038/ncomms6767
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    Cited by:

    1. Raphaël Dos Reis & Etienne Kornobis & Alyssa Pereira & Frederic Tores & Judit Carrasco & Candice Gautier & Céline Jahannault-Talignani & Patrick Nitschké & Christian Muchardt & Andreas Schlosser & Han, 2022. "Complex regulation of Gephyrin splicing is a determinant of inhibitory postsynaptic diversity," Nature Communications, Nature, vol. 13(1), pages 1-17, December.

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