Gephyrin-binding peptides visualize postsynaptic sites and modulate neurotransmission

Research output: Contribution to journalJournal articleResearchpeer-review

  • Hans Michael Maric
  • Torben Johann Hausrat
  • Franziska Neubert
  • Nils Ole Dalby
  • Sören Doose
  • Markus Sauer
  • Matthias Kneussel
  • Strømgaard, Kristian

γ-Aminobutyric acid type A and glycine receptors are the major mediators of fast synaptic inhibition in the human central nervous system and are established drug targets. However, all drugs targeting these receptors bind to the extracellular ligand-binding domain of the receptors, which inherently is associated with perturbation of the basic physiological action. Here we pursue a fundamentally different approach, by instead targeting the intracellular receptor-gephyrin interaction. First, we defined the gephyrin peptide-binding consensus sequence, which facilitated the development of gephyrin super-binding peptides and later effective affinity probes for the isolation of native gephyrin. Next, we demonstrated that fluorescent super-binding peptides could be used to directly visualize inhibitory postsynaptic sites for the first time in conventional and super-resolution microscopy. Finally, we demonstrate that the gephyrin super-binding peptides act as acute intracellular modulators of fast synaptic inhibition by modulating receptor clustering, thus being conceptually novel modulators of inhibitory neurotransmission.

Original languageEnglish
Article number2246
JournalNature Chemical Biology
Pages (from-to)153-160
Number of pages11
Publication statusPublished - 2017

ID: 169435827