RGD Reference Report - Multiple molecular interactions determine the clustering of Caspr2 and Kv1 channels in myelinated axons. - Rat Genome Database

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Multiple molecular interactions determine the clustering of Caspr2 and Kv1 channels in myelinated axons.

Authors: Horresh, I  Poliak, S  Grant, S  Bredt, D  Rasband, MN  Peles, E 
Citation: Horresh I, etal., J Neurosci. 2008 Dec 24;28(52):14213-22. doi: 10.1523/JNEUROSCI.3398-08.2008.
RGD ID: 8554606
Pubmed: PMID:19109503   (View Abstract at PubMed)
PMCID: PMC2859216   (View Article at PubMed Central)
DOI: DOI:10.1523/JNEUROSCI.3398-08.2008   (Journal Full-text)

Clustering of Kv1 channels at the juxtaparanodal region (JXP) in myelinated axons depends on their association with the Caspr2/TAG-1 adhesion complex. The interaction between these channels and Caspr2 was suggested to depend on PDZ (PSD-95/Discs large/zona occludens-1) scaffolding proteins. Here, we show that at a subset of the JXP, PSD-93 colocalizes with Caspr2, K(+) channels and its related protein postsynaptic density protein-95 (PSD-95). The localization of PSD-93 and PSD-95 depends on the presence of Caspr2, as both scaffolding proteins failed to accumulate at the JXP in mice lacking either Caspr2 or TAG-1. In contrast, Caspr2 and K(+) channels still colocalized and associated in PSD-93, PSD-95 or double PSD-93/PSD-95 null mice. To directly evaluate the role of PDZ domain proteins in the function of Caspr2, we examined the ability of transgenic Caspr2 molecules lacking either their cytoplasmic domain (Caspr2dCT), or their PDZ-binding sequence (Caspr2dPDZ), to restore Kv1 channel clustering in Caspr2 null mice. We found that while Kv1 channels were distributed throughout internodes in nerves expressing Caspr2dCT, they were clustered at the JXP in axons expressing a full-length Caspr2 (Caspr2FL) or the Caspr2dPDZ transgene. Further proteomic analysis revealed that Caspr2 interacts with a distinct set of scaffolding proteins through its PDZ- and protein 4.1-binding sequences. These results demonstrate that while the molecular assembly of the JXP requires the cytoplasmic domain of Caspr2, its carboxy-terminal PDZ-binding motif is dispensable for Kv1 channel clustering. This mechanism is clearly distinct from the one operating at the axon initial segment, which requires PSD-93 for Kv1 channel clustering.



Gene Ontology Annotations    Click to see Annotation Detail View

Cellular Component

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Dlg2Ratjuxtaparanode region of axon located_inIDA PMID:19109503MGI 
Dlg4Ratjuxtaparanode region of axon located_inIDA PMID:19109503MGI 

Objects Annotated

Genes (Rattus norvegicus)
Dlg2  (discs large MAGUK scaffold protein 2)
Dlg4  (discs large MAGUK scaffold protein 4)


Additional Information