| Sodium channels mediate electrical signals in excitable tissues. In mammals, sodium channels are encoded by nine genes, whose products are designated Na v1.1 to Nav1.9. In myelinated nerves, Nav1.6 populates nodes of Ranvier and is responsible for the saltatory conduction of nervous impulse, which is characteristic of these axons. However, during development, a transition from Nav1.2 to Nav1.6 expression occurs at nodes of Ranvier, and myelination has been implied to play a role in this switch. Thus two questions arise: (1) are other sodium channel isoforms also present in developing nodes, and (2) how is the Nav1.6 isoform-specific sodium channel expression at nodes actually regulated?; By immunizing rabbits with artificially-synthesized peptides that represent unique amino acid sequences in each sodium channel isoform, we generated polyclonal antibodies against every neuronal sodium channel subtype (except Nav 1.1, for which an adequate antibody was available commercially). Using these antibodies, I examined nodal sodium channel isoform expression in developing sciatic nerves of wild-type mice. I found that most neuronal sodium channel isoforms were present in early nodes, but with development, Nav1.6 gradually became predominant and other subtypes diminished at nodes.; To determine how such isoform transition is regulated, I investigated nodal expression of various sodium channel isoforms in developing sciatic nerves of a Schwann cell-specific Oct-6 mutant, whose PNS myelination was transiently delayed for about 10 days. I found that the delayed myelination not only retarded nodal sodium channel cluster formation, but also suppressed the expression of Nav1.2 and Nav1.7 in developing nodes. However, the delayed myelination did not affect neuronal synthesis or transport of sodium channels. Furthermore, in agreement with the replacement of Na v1.2 by Nav1.6 in developing nodes, the transcription of these two isoforms in DRGs as well as their abundance in the sciatic nerves changed reciprocally with development. Thus, I proposed an 'isoform dilution' model to explain the nodal isoform transition. That is, all sodium channel isoforms share similar ability to inhabit in nodes, and their presence at nodes relies on their relative abundance in axons. Nav1.6 predominates in adult nodes because its level relative to other isoforms gradually increases in developing axons. |
