The sodium channel isoform transition at developing nodes of ranvier in the peripheral nervous system: Dependence on a Genetic program and myelination‐induced cluster formation

Abstract

Among sodium channel isoforms, Nav 1.6 is selectively expressed at nodes of Ranvier in both the CNS and the PNS. However, non-Nav 1.6 isoforms such as Nav 1.2 are also present at the CNS nodes in early development but gradually diminish later. It has been proposed that myelination is part of a glia-neuron signaling mechanism that produces this change in nodal isoform expression. The present study used isoform-specific antibodies to demonstrate that, in the PNS, four other neuronal sodium channel isoforms were also clustered at nodes in early development but eventually disappeared during maturation. To study possible roles of myelination in such transitions, we investigated the nodal expression of selected isoforms in the sciatic nerve of the transgenic mouse Oct6(ΔSCE/βgeo) , whose PNS myelination is delayed in the first postnatal week but eventually resumes. We found that delayed myelination retarded the formation of nodal channel clusters and altered the expression-elimination patterns of sodium channel isoforms, resulting in significantly reduced expression levels of non-Nav 1.6 isoforms in such delayed nodes. However, delayed myelination did not significantly affect the gene expression, protein synthesis, or axonal trafficking of any isoform studied. Rather, we found evidence for a developmentally programmed increase in neuronal Nav 1.6 expression with constant or decreasing neuronal expression of other isoforms that were unaffected by delayed myelination. Thus our results suggest that, in the developmental isoform switch of the PNS, myelination does not play a signaling role as that proposed for the CNS but rather serves only to form nodal clusters from existing isoform pools.

Axons provide the secretory machinery for trafficking of voltage-gated sodium channels in peripheral nerve

“…More importantly, NaV1.6 and β2-NaV were expressed in the sciatic nerve in agreement with their expression in mature axons (Fig. 4A, Upper) (31). P0 was also detected in these samples indicating that Schwann cell material is part of the preparation and therefore that it cannot be used to nonambiguously define axonal transcripts.…”

Mechanisms of sodium channel clustering and its influence on axonal impulse conduction

“…Na v 1.2, which is primarily associated to the mammalian immature PNS and CNS nodal-like clusters and nodes of Ranvier [ 11 , 92 , 130 , 132 , 133 ] needs large depolarizing current to fire and inactivates during high-frequency firing [ 134 ]. Na v 1.6 and Na v 1.1, which are clustered to mature nodes of Ranvier and nodal-like clusters in the PNS and CNS [ 11 , 130 , 131 , 133 , 135 ], participate in persistent sodium current [ 134 , 136 , 137 ]. This slowly inactivating current may therefore drive faster conduction through the increase of axoplasmic Na + [ 134 , 137 – 139 ].…”

Scorpion toxin MeuNaTxα‐1 sensitizes primary nociceptors by selective modulation of voltage‐gated sodium channels

“…Scorpion α‐toxins such as MeuNaTxα‐1 target VGSC isoforms whose expression pattern changes during the postnatal maturation of the peripheral nervous system [40]. We therefore tested if MeuNaTxα‐1 elicits a different signaling response in DRG neurons from newborn rats (P2–P4).…”

“…Na V 1.1, 1.2, 1.6, 1.7, and 1.8 are clustered at nodes of Ranvier in the sciatic nerve of wild‐type mice at postnatal days 4–7 (P4–P7) [40]. Specifically, Na V 1.2 clustering peaks at P4 and declines by P14.…”