title: Gephyrin-binding peptides visualize postsynaptic sites and modulate neurotransmission.
abstract: 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.
authors.affiliation: Center for Biopharmaceuticals, Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Hans Michael
authors.initials: HM
authors.lastname: Maric
authors.affiliation: Department of Molecular Neurogenetics, Center for Molecular Neurobiology, ZMNH, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Torben Johann
authors.initials: TJ
authors.lastname: Hausrat
authors.affiliation: Department of Biotechnology and Biophysics, Biocenter, University of Würzburg, Würzburg, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Neubert
authors.affiliation: Center for Biopharmaceuticals, Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Nils Ole
authors.initials: NO
authors.lastname: Dalby
authors.affiliation: Department of Biotechnology and Biophysics, Biocenter, University of Würzburg, Würzburg, Germany.
authors.forename: Sören
authors.initials: S
authors.lastname: Doose
authors.affiliation: Department of Biotechnology and Biophysics, Biocenter, University of Würzburg, Würzburg, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Sauer
authors.affiliation: Department of Molecular Neurogenetics, Center for Molecular Neurobiology, ZMNH, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Kneussel
authors.affiliation: Center for Biopharmaceuticals, Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Kristian
authors.identifier: 0000-0003-2206-4737
authors.initials: K
authors.lastname: Strømgaard
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism*; D002478:Cells, Cultured; D057809:HEK293 Cells; D006801:Humans; D049449:Luminescence; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D010455:Peptides / Q000032:analysis* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D013569:Synapses / Q000187:drug effects* / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects*
chemical_list: D002352:Carrier Proteins; D008565:Membrane Proteins; D010455:Peptides; C073441:gephyrin