Paranodal transverse bands are required for maintenance but not initiation of Nav1.6 sodium channel clustering in CNS optic nerve axons.
The rapid, efficient, and faithful propagation of action potentials in myelinated nerve fibers depends on the appropriate complement and localization of ion channels. Recent work has suggested that specific voltage-dependent sodium (Nav) channel isoforms are differentially regulated both spatially and temporally in a myelin-dependent manner. Since the principal site of axoglial contact occurs at the paranode, we postulated that disrupted paranodal structure might result in altered nodal Nav channel isoform localization and clustering. We have used UDP-galactose/ceramide galactosyl transferase (CGT)-deficient mice, which form compact myelin and paranodal loops but lack the transverse bands normally found at the interface of the axon and overlying glial cell, to determine if this structure contributes to the signaling machinery responsible for clustering and localization of distinct Nav channel isoforms. We find that as in control animals, most mutant nodes of Ranvier had Nav1.6 in high-density clusters in the peripheral and central nervous systems; the localization of Nav1.2 and the protein levels of Nav1.2 and Nav1.6 were also normal in the CGT-deficient mouse. However, with increasing age, in the mutant mouse we observed a decrease in the total number of nodal Nav1.6 clusters, a decrease in the density of Nav1.6 channels at nodes, and an increase in the average size of the Nav1.6 clusters. Thus, transverse bands are not required for Nav1.6 clustering and localization at nodes or for exclusion of Nav1.2 from myelinated nerve fibers, but are required for the maintenance of nodal Nav1.6 cluster size and density.
D000367:Age Factors; D000595:Amino Acid Sequence; D000818:Animals; D001369:Axons / Q000737:chemistry / Q000378:metabolism*; D002490:Central Nervous System / Q000737:chemistry / Q000166:cytology / Q000378:metabolism; D005700:Galactosyltransferases / Q000172:deficiency / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009186:Myelin Sheath / Q000737:chemistry / Q000378:metabolism*; D051146:N-Acylsphingosine Galactosyltransferase; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D009900:Optic Nerve / Q000737:chemistry / Q000166:cytology / Q000378:metabolism*; D011901:Ranvier's Nodes / Q000737:chemistry / Q000378:metabolism*; D015222:Sodium Channels / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics
D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C491046:Scn8a protein, mouse; D015222:Sodium Channels; D005700:Galactosyltransferases; D051146:N-Acylsphingosine Galactosyltransferase