Neurexins: molecular codes for shaping neuronal synapses.
#Snapgene lenticrispr v2 map code
Synaptic neurexin complexes: a molecular code for the logic of neural circuits. Exome sequencing identifies rare coding variants in 10 genes which confer substantial risk for schizophrenia. The origin of NMDA receptor hypofunction in schizophrenia. AMPARs and synaptic plasticity: the last 25 years. Creating diverse synapses from the same molecules. Architecture of the mouse brain synaptome. Presynaptic neurexin-3 alternative splicing trans-synaptically controls postsynaptic AMPA receptor trafficking. Alternative splicing of presynaptic neurexins differentially controls postsynaptic NMDA and AMPA receptor responses. Cbln1 is a ligand for an orphan glutamate receptor δ2, a bidirectional synapse organizer. Differential interactions of cerebellin precursor protein (Cbln) subtypes and neurexin variants for synapse formation of cortical neurons. Trans-synaptic interaction of GluRδ2 and Neurexin through Cbln1 mediates synapse formation in the cerebellum. 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. The distinct signalling specificity of presynaptic neurexin-1 and neurexin-3 5, 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. 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. 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. Here we show in hippocampal synapses, that binding of presynaptic neurexin–cerebellin complexes to postsynaptic GluD1 controls glutamate receptor activity without affecting synapse numbers. It is unclear whether neurexin–cerebellin–GluD1/2 assemblies serve an adhesive synapse-formation function or mediate trans-synaptic signalling. 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 neurexins 1, 2, 3, 4.
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