Molecular Mechanisms for K+ channel clustering on myelinated axons

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The characteristic localization of ion channels is crucial for the propagation of saltatory conductions in myelinated nerves. The voltage-gated Na+ channels located at Node of Ranvier while the voltage-gated K+ channels are mainly found at juxtaparanodal regions. From our present studies, the K+ channel clustering in the CNS is well correlated with the formation of myelin sheath on the axons, but not with the association of oligodendrocyte cell bodies, suggesting that, in contrast to Na+ channel clustering, contact of the myelin membrane onto the axons is important for K+ channels clustering. To identify the molecular mechanisms for K+ channel clustering, the localization of PSD-95 was examined both in normal and demyelinated axons. PSD-95, which is known to bind K+ channels and NMDA receptors and form clusters of these proteins at post synaptic densities, was colocalized with K+ channel in the juxtaparanodal regions. In demyelinated axons, the clustering of both PSD-95 and K+ channels disappeared, but the total amount of both proteins as judged by the Western blotting did not change, indicating that they redistributed diffusely. From transfection studies using cDNAs of K+ channel subunits and PSD-95, we found that another factors may be required for the cluster formation of these proteins in the appropriate places in the axons. The localizations of two newly identified proteins around the nodes, Caspr (paranode), and Caspr2 (juxtaparanode), were also examined, and were found to be well corelated with K+ channel clustering and the paranodal junctional formation was also important for their characteristic localization. These results suggested that these two proteins may also be involved in K+ channel clustering in addition to PSD-95.