Neurexins physically and functionally interact with GABA(A) 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.
Zhang
Chen
C
Department of Molecular and Cellular Physiology, Stanford University, 1050 Arastradero Road, Palo Alto, CA 94304-5543, USA.
Atasoy
Deniz
D
Araç
Demet
D
Yang
Xiaofei
X
Fucillo
Marc V
MV
Robison
Alfred J
AJ
Ko
Jaewon
J
Brunger
Axel T
AT
Südhof
Thomas C
TC
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
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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