GluD1 is a signal transduction device disguised as an ionotropic receptor
GluD1 is a signal transduction device disguised as an ionotropic receptor
Ionotropic glutamate delta receptors 1 (GluD1) and 2 (GluD2) exhibit the molecular architecture of postsynaptic ionotropic glutamate receptors, but assemble into trans-synaptic adhesion complexes by binding to secreted cerebellins that in turn interact with presynaptic neurexins1-4. It is unclear whether neurexin-cerebellin-GluD1/2 assemblies serve an adhesive synapse-formation function or mediate trans-synaptic signalling. Here we show in hippocampal synapses, that binding of presynaptic neurexin-cerebellin complexes to postsynaptic GluD1 controls glutamate receptor activity without affecting synapse numbers. Specifically, neurexin-1-cerebellin-2 and neurexin-3-cerebellin-2 complexes differentially regulate NMDA (N-methyl-D-aspartate) receptors and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors by activating distinct postsynaptic GluD1 effector signals. Of note, minimal GluD1 and GluD2 constructs containing only their N-terminal cerebellin-binding and C-terminal cytoplasmic domains, joined by an unrelated transmembrane region, fully control the levels of NMDA and AMPA receptors. The distinct signalling specificity of presynaptic neurexin-1 and neurexin-35,6 is encoded by their alternatively spliced splice site 4 sequences, whereas the regulatory functions of postsynaptic GluD1 are mediated by conserved cytoplasmic sequence motifs spanning 5-13 residues. Thus, GluDs are signalling molecules that regulate NMDA and AMPA receptors by an unexpected transduction mechanism that bypasses their ionotropic receptor architecture and directly converts extracellular neurexin-cerebellin signals into postsynaptic receptor responses.
Amino Acid Motifs, Animals, Calcium-Binding Proteins/metabolism, Cell Membrane/metabolism, Excitatory Postsynaptic Potentials, Female, Glutamate Dehydrogenase/metabolism, Male, Mice, Nerve Tissue Proteins/metabolism, Neural Cell Adhesion Molecules/metabolism, Protein Precursors/metabolism, Receptors, AMPA/metabolism, Receptors, Ionotropic Glutamate/metabolism, Receptors, N-Methyl-D-Aspartate/metabolism, Signal Transduction, Synapses/metabolism
261-265
Dai, Jinye
a95968c4-ee52-4e37-a88d-e411b1835e9f
Patzke, Christopher
77693ddf-01e4-409b-aa5f-3429ba7c8cd5
Liakath-Ali, Kif
8d5a020c-e976-4901-9195-68f4bc0de74e
Seigneur, Erica
6d8b2df1-ab72-4d7e-9ae2-2e4cbc2f9d8e
Südhof, Thomas C.
172ec4da-ad42-4b1f-bd99-6b7d288e040c
July 2021
Dai, Jinye
a95968c4-ee52-4e37-a88d-e411b1835e9f
Patzke, Christopher
77693ddf-01e4-409b-aa5f-3429ba7c8cd5
Liakath-Ali, Kif
8d5a020c-e976-4901-9195-68f4bc0de74e
Seigneur, Erica
6d8b2df1-ab72-4d7e-9ae2-2e4cbc2f9d8e
Südhof, Thomas C.
172ec4da-ad42-4b1f-bd99-6b7d288e040c
Dai, Jinye, Patzke, Christopher, Liakath-Ali, Kif, Seigneur, Erica and Südhof, Thomas C.
(2021)
GluD1 is a signal transduction device disguised as an ionotropic receptor.
Nature, 595 (7866), .
(doi:10.1038/s41586-021-03661-6).
Abstract
Ionotropic glutamate delta receptors 1 (GluD1) and 2 (GluD2) exhibit the molecular architecture of postsynaptic ionotropic glutamate receptors, but assemble into trans-synaptic adhesion complexes by binding to secreted cerebellins that in turn interact with presynaptic neurexins1-4. It is unclear whether neurexin-cerebellin-GluD1/2 assemblies serve an adhesive synapse-formation function or mediate trans-synaptic signalling. Here we show in hippocampal synapses, that binding of presynaptic neurexin-cerebellin complexes to postsynaptic GluD1 controls glutamate receptor activity without affecting synapse numbers. Specifically, neurexin-1-cerebellin-2 and neurexin-3-cerebellin-2 complexes differentially regulate NMDA (N-methyl-D-aspartate) receptors and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors by activating distinct postsynaptic GluD1 effector signals. Of note, minimal GluD1 and GluD2 constructs containing only their N-terminal cerebellin-binding and C-terminal cytoplasmic domains, joined by an unrelated transmembrane region, fully control the levels of NMDA and AMPA receptors. The distinct signalling specificity of presynaptic neurexin-1 and neurexin-35,6 is encoded by their alternatively spliced splice site 4 sequences, whereas the regulatory functions of postsynaptic GluD1 are mediated by conserved cytoplasmic sequence motifs spanning 5-13 residues. Thus, GluDs are signalling molecules that regulate NMDA and AMPA receptors by an unexpected transduction mechanism that bypasses their ionotropic receptor architecture and directly converts extracellular neurexin-cerebellin signals into postsynaptic receptor responses.
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Accepted/In Press date: 20 May 2021
e-pub ahead of print date: 16 June 2021
Published date: July 2021
Keywords:
Amino Acid Motifs, Animals, Calcium-Binding Proteins/metabolism, Cell Membrane/metabolism, Excitatory Postsynaptic Potentials, Female, Glutamate Dehydrogenase/metabolism, Male, Mice, Nerve Tissue Proteins/metabolism, Neural Cell Adhesion Molecules/metabolism, Protein Precursors/metabolism, Receptors, AMPA/metabolism, Receptors, Ionotropic Glutamate/metabolism, Receptors, N-Methyl-D-Aspartate/metabolism, Signal Transduction, Synapses/metabolism
Identifiers
Local EPrints ID: 491450
URI: http://eprints.soton.ac.uk/id/eprint/491450
ISSN: 0028-0836
PURE UUID: 51aceda2-a1e9-4742-a73d-0acfe34b3024
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Date deposited: 24 Jun 2024 16:49
Last modified: 25 Jun 2024 02:10
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Contributors
Author:
Jinye Dai
Author:
Christopher Patzke
Author:
Kif Liakath-Ali
Author:
Erica Seigneur
Author:
Thomas C. Südhof
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