title: Palmitoylation of gephyrin controls receptor clustering and plasticity of GABAergic synapses.
abstract: Postsynaptic scaffolding proteins regulate coordinated neurotransmission by anchoring and clustering receptors and adhesion molecules. Gephyrin is the major instructive molecule at inhibitory synapses, where it clusters glycine as well as major subsets of GABA type A receptors (GABAARs). Here, we identified palmitoylation of gephyrin as an important mechanism of strengthening GABAergic synaptic transmission, which is regulated by GABAAR activity. We mapped palmitoylation to Cys212 and Cys284, which are critical for both association of gephyrin with the postsynaptic membrane and gephyrin clustering. We identified DHHC-12 as the principal palmitoyl acyltransferase that palmitoylates gephyrin. Furthermore, gephyrin pamitoylation potentiated GABAergic synaptic transmission, as evidenced by an increased amplitude of miniature inhibitory postsynaptic currents. Consistently, inhibiting gephyrin palmitoylation either pharmacologically or by expression of palmitoylation-deficient gephyrin reduced the gephyrin cluster size. In aggregate, our study reveals that palmitoylation of gephyrin by DHHC-12 contributes to dynamic and functional modulation of GABAergic synapses.
authors.affiliation: Institute of Biochemistry, Department of Chemistry, University of Cologne, Cologne, Germany.
authors.forename: Borislav
authors.initials: B
authors.lastname: Dejanovic
authors.affiliation: RNA Editing and Hyperexcitability Disorders Helmholtz Group, Max Delbrück Center for Molecular Medicine, Berlin, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Semtner
authors.affiliation: Institute of Biochemistry, Department of Chemistry, University of Cologne, Cologne, Germany.
authors.forename: Silvia
authors.initials: S
authors.lastname: Ebert
authors.affiliation: Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Lamkemeyer
authors.affiliation: Institute of Biochemistry, Department of Chemistry, University of Cologne, Cologne, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Neuser
authors.affiliation: Department of Biology and Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, Pennsylvania, United States of America.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Lüscher
authors.affiliation: RNA Editing and Hyperexcitability Disorders Helmholtz Group, Max Delbrück Center for Molecular Medicine, Berlin, Germany.
authors.forename: Jochen C
authors.initials: JC
authors.lastname: Meier
authors.affiliation: Institute of Biochemistry, Department of Chemistry, University of Cologne, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
authors.forename: Guenter
authors.initials: G
authors.lastname: Schwarz
mesh_terms: D000217:Acyltransferases / Q000502:physiology*; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D003545:Cysteine / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D054878:Lipoylation / Q000502:physiology*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D009473:Neuronal Plasticity / Q000502:physiology*; D011963:Receptors, GABA-A / Q000378:metabolism*; D013569:Synapses / Q000502:physiology*; D005680:gamma-Aminobutyric Acid
chemical_list: D002352:Carrier Proteins; D008565:Membrane Proteins; D011963:Receptors, GABA-A; C073441:gephyrin; D005680:gamma-Aminobutyric Acid; D000217:Acyltransferases; C000595445:ZDHHC12 protein, human; D003545:Cysteine