title: Pin1-dependent signalling negatively affects GABAergic transmission by modulating neuroligin2/gephyrin interaction.
abstract: The cell adhesion molecule Neuroligin2 (NL2) is localized selectively at GABAergic synapses, where it interacts with the scaffolding protein gephyrin in the post-synaptic density. However, the role of this interaction for formation and plasticity of GABAergic synapses is unclear. Here, we demonstrate that endogenous NL2 undergoes proline-directed phosphorylation at its unique S714-P consensus site, leading to the recruitment of the peptidyl-prolyl cis-trans isomerase Pin1. This signalling cascade negatively regulates NL2's ability to interact with gephyrin at GABAergic post-synaptic sites. As a consequence, enhanced accumulation of NL2, gephyrin and GABAA receptors was detected at GABAergic synapses in the hippocampus of Pin1-knockout mice (Pin1-/-) associated with an increase in amplitude of spontaneous GABAA-mediated post-synaptic currents. Our results suggest that Pin1-dependent signalling represents a mechanism to modulate GABAergic transmission by regulating NL2/gephyrin interaction.
authors.affiliation: Department of Neuroscience, International School for Advanced Studies (SISSA), via Bonomea 265, 34136 Trieste, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Antonelli
authors.affiliation: Department of Neuroscience, International School for Advanced Studies (SISSA), via Bonomea 265, 34136 Trieste, Italy.
authors.forename: Rocco
authors.initials: R
authors.lastname: Pizzarelli
authors.affiliation: Department of Neuroscience, International School for Advanced Studies (SISSA), via Bonomea 265, 34136 Trieste, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Pedroni
authors.affiliation: Institute of Pharmacology and Toxicology, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Fritschy
authors.affiliation: 1] Laboratorio Nazionale del Consorzio Interuniversitario per le Biotecnologie (LNCIB), Padriciano 99, 34012 Trieste, Italy [2] Dipartimento di Scienze della vita, Universita' degli Studi di Trieste, Trieste, Italy.
authors.forename: Giannino
authors.initials: G
authors.lastname: Del Sal
authors.affiliation: 1] Department of Neuroscience, International School for Advanced Studies (SISSA), via Bonomea 265, 34136 Trieste, Italy [2] European Brain Research Institute (EBRI), via del Fosso di Fiorano 64, 00143 Rome, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Cherubini
authors.affiliation: Department of Neuroscience, International School for Advanced Studies (SISSA), via Bonomea 265, 34136 Trieste, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Zacchi
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism*; D059330:GABAergic Neurons / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D019696:Peptidylprolyl Isomerase / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D057907:Post-Synaptic Density / Q000378:metabolism*; D011963:Receptors, GABA-A / Q000378:metabolism*; D015398:Signal Transduction; D013569:Synapses / Q000378:metabolism; D009435:Synaptic Transmission / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D015816:Cell Adhesion Molecules, Neuronal; D008565:Membrane Proteins; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009419:Nerve Tissue Proteins; D011963:Receptors, GABA-A; C073441:gephyrin; C098003:neuroligin 2; D005680:gamma-Aminobutyric Acid; D019696:Peptidylprolyl Isomerase; C000606850:Pin1 protein, mouse