Neurexins Physically and Functionally Interact with GABAA Receptors
Copyright policy )Neurexins Physically and Functionally Interact with GABAA Receptors
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.
- Stanford University United States
- Howard Hughes Medical Institute
- Howard Hughes Medical Institute United States
- Icahn School of Medicine at Mount Sinai United States
- The University of Texas Southwestern Medical Center United States
Neuroscience(all), Blotting, Western, Cell Culture Techniques, Fluorescent Antibody Technique, Glutamic Acid, Nerve Tissue Proteins, Hippocampus, MOLNEURO, Cell Line, Mice, Animals, Humans, Immunoprecipitation, Protein Interaction Domains and Motifs, Cells, Cultured, Neurons, Excitatory Postsynaptic Potentials, Receptors, GABA-A, Immunohistochemistry, Coculture Techniques, Inhibitory Postsynaptic Potentials, SIGNALING, CELLBIO, Cell Adhesion Molecules
Neuroscience(all), Blotting, Western, Cell Culture Techniques, Fluorescent Antibody Technique, Glutamic Acid, Nerve Tissue Proteins, Hippocampus, MOLNEURO, Cell Line, Mice, Animals, Humans, Immunoprecipitation, Protein Interaction Domains and Motifs, Cells, Cultured, Neurons, Excitatory Postsynaptic Potentials, Receptors, GABA-A, Immunohistochemistry, Coculture Techniques, Inhibitory Postsynaptic Potentials, SIGNALING, CELLBIO, Cell Adhesion Molecules
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