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The Journal of Neuroscience, December 24, 2008, 28(52):14213-14222; doi:10.1523/JNEUROSCI.3398-08.2008

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Cellular/Molecular
Multiple Molecular Interactions Determine the Clustering of Caspr2 and Kv1 Channels in Myelinated Axons

Ido Horresh,¹ Sebastian Poliak,¹ Seth Grant,² David Bredt,³ Matthew N. Rasband,⁴ and Elior Peles¹

¹Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel, ²The Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom, ³Department of Integrative Biology, Eli Lilly and Company, Indianapolis, Indiana 46285, and ⁴Department of Neuroscience, Baylor College of Medicine, Houston, Texas 77030

Correspondence should be addressed to Dr. Elior Peles, Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel. Email: peles{at}weizmann.ac.il

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.

Key words: nodes of Ranvier; axon initial segment; PSD-93; PSD-95; juxtaparanodes; scaffolding proteins

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Received July 21, 2008; revised Oct. 22, 2008; accepted Nov. 8, 2008.

Correspondence should be addressed to Dr. Elior Peles, Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel. Email: peles{at}weizmann.ac.il

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