GluRδ2 assembles four neurexins into trans-synaptic triad to trigger synapse formation.
J Neurosci
; 32(13): 4688-701, 2012 Mar 28.
Article
em En
| MEDLINE
| ID: mdl-22457515
ABSTRACT
Elucidation of molecular mechanisms of synapse formation is a prerequisite for the understanding of neural wiring, higher brain functions, and mental disorders. The trans-synaptic interaction of postsynaptic glutamate receptor δ2 (GluRδ2) and presynaptic neurexins (NRXNs) through cerebellin precursor protein 1 (Cbln1) mediates synapse formation in vivo in the cerebellum. Here, we asked how the trans-synaptic triad induces synapse formation. Native GluRδ2 existed as a tetramer in the membrane, whereas the N-terminal domain (NTD) of GluRδ2 formed a stable homodimer. When incubated with cultured mouse cerebellar granule cells (GCs), dimeric GluRδ2-NTD and Cbln1 exerted little effect on the accumulation of punctate immunostaining signals for Bassoon and vesicular glutamate transporter 1 in GC axons. However, tetramerized GluRδ2-NTD stimulated the accumulation of these presynaptic proteins in the axons. Analysis of Cbln1 mutants suggested that the binding sites of GluRδ2 and NRXN1ß on Cbln1 are differential. Furthermore, there was no competition in the binding to Cbln1 between GluRδ2-NTD and the extracellular domain (ECD) of NRXN1ß. Thus, GluRδ2 and Cbln1 interacted with each other rather independently of Cbln1-NRXN1ß interaction and vice versa. Gel filtration and isothermal titration calorimetry analyses consistently showed that dimeric GluRδ2-NTD and hexameric Cbln1 assembled in the 11 ratio, whereas hexameric Cbln1 and the laminin-neurexin-sex hormone-binding globulin domain of NRXN1ß-ECD assembled in the 12 ratio. Thus, the synaptogenic triad is assembled from tetrameric GluRδ2, hexameric Cbln1, and monomeric NRXN in the ratio of 124. These results suggest that GluRδ2 triggers synapse formation by clustering four NRXNs through triad formation.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Sinapses
/
Neuropeptídeos
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Glicoproteínas
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Receptores de Glutamato
Limite:
Animals
Idioma:
En
Ano de publicação:
2012
Tipo de documento:
Article