title: Neurexins physically and functionally interact with GABA(A) receptors.
abstract: Neurexins are presynaptic cell-adhesion molecules that form trans-synaptic complexes with postsynaptic neuroligins. When overexpressed in nonneuronal cells, neurexins induce formation of postsynaptic specializations in cocultured neurons, suggesting that neurexins are synaptogenic. However, we find that when overexpressed in neurons, neurexins do not increase synapse density, but instead selectively suppressed GABAergic synaptic transmission without decreasing GABAergic synapse numbers. This suppression was mediated by all subtypes of neurexins tested, in a cell-autonomous and neuroligin-independent manner. Strikingly, addition of recombinant neurexin to cultured neurons at submicromolar concentrations induced the same suppression of GABAergic synaptic transmission as neurexin overexpression. Moreover, experiments with native brain proteins and purified recombinant proteins revealed that neurexins directly and stoichiometrically bind to GABA(A) receptors, suggesting that they decrease GABAergic synaptic responses by interacting with GABA(A) receptors. Our findings suggest that besides their other well-documented interactions, presynaptic neurexins directly act on postsynaptic GABA(A) receptors, which may contribute to regulate the excitatory/inhibitory balance in brain.
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University, 1050 Arastradero Road, Palo Alto, CA 94304-5543, USA.
authors.forename: Chen
authors.initials: C
authors.lastname: Zhang
authors.forename: Deniz
authors.initials: D
authors.lastname: Atasoy
authors.forename: Demet
authors.initials: D
authors.lastname: Araç
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Yang
authors.forename: Marc V
authors.initials: MV
authors.lastname: Fucillo
authors.forename: Alfred J
authors.initials: AJ
authors.lastname: Robison
authors.forename: Jaewon
authors.initials: J
authors.lastname: Ko
authors.forename: Axel T
authors.initials: AT
authors.lastname: Brunger
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Südhof
mesh_terms: D000818:Animals; D015153:Blotting, Western; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D018929:Cell Culture Techniques; D002460:Cell Line; D002478:Cells, Cultured; D018920:Coculture Techniques; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D005455:Fluorescent Antibody Technique; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D053444:Inhibitory Postsynaptic Potentials / Q000502:physiology; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D054730:Protein Interaction Domains and Motifs / Q000502:physiology*; D011963:Receptors, GABA-A / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013569:Synapses / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D015815:Cell Adhesion Molecules; D009419:Nerve Tissue Proteins; D011963:Receptors, GABA-A; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid
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