Paranodal Interactions Regulate Expression of Sodium Channel Subtypes and Provide a Diffusion Barrier for the Node of Ranvier

Abstract

The node of Ranvier is a distinct domain of myelinated axons that is highly enriched in sodium channels and is critical for impulse propagation. During development, the channel subtypes expressed at the node undergo a transition from Nav1.2 to Nav1.6. Specialized junctions that form between the paranodal glial membranes and axon flank the nodes and are candidates to regulate their maturation and delineate their boundaries. To investigate these roles, we characterized node development in mice deficient in contactin-associated protein (Caspr), an integral junctional component. Paranodes in these mice lack transverse bands, a hallmark of the mature junction, and exhibit progressive disruption of axon-paranodal loop interactions in the CNS. Caspr mutant mice display significant abnormalities at central nodes; components of the nodes progressively disperse along axons, and many nodes fail to mature properly, persistently expressing Nav1.2 rather than Nav1.6. In contrast, PNS nodes are only modestly longer and, although maturation is delayed, eventually all express Nav1.6. Potassium channels are aberrantly clustered in the paranodes; these clusters are lost over time in the CNS, whereas they persist in the PNS. These findings indicate that interactions of the paranodal loops with the axon promote the transition in sodium channel subtypes at CNS nodes and provide a lateral diffusion barrier that, even in the absence of transverse bands, maintains a high concentration of components at the node and the integrity of voltage-gated channel domains.

Electron tomographic analysis of cytoskeletal cross-bridges in the paranodal region of the node of Ranvier in peripheral nerves

“…In our reconstructions, the PJBs were only occasionally observed as discrete pegs, but more often formed a continuous rod of density. This appearance conforms to the role described for PJBs as septate-like junctions that serve in a paracellular capacity to block the diffusion of ions and channels between the paranodal and juxtaparanodal areas (Rios et al, 2003;Salzer, 2003).…”

Contactin-1 regulates myelination and nodal/paranodal domain organization in the central nervous system

“…Similar to the periphery (12), in Cntn1-KO CNS we observed disrupted paranodal junctions characterized by loss of Caspr and mislocalization of the shaker-type potassium K v 1.2 channels that normally define juxtaparanodal regions (1,26). These defects parallel the paranodal deficiencies in Casprand UDP-galactose:ceramide galactosyltransferase (CGT)-KO mice, and indicate complete loss of paranodal functions as diffusion barriers for voltage-gated Na v and K v channels (44)(45)(46). Several studies queried if paranodal assembly is necessary for myelination.…”

“…Disruption of paranodes, as in Caspr-and CGT-KO mice, does not drastically reduce nodal numbers but distorts their shapes and maturation. This finding suggests that paranodes regulate tightness and maturation, but not the frequency of nodal clusters (45,46,(48)(49)(50). Nodal numbers are significantly reduced in the Caspr-KO background only in combination with additional mutations: disrupted βIV-spectrin, which anchors sodium channels to the cytoskeleton, or ECM proteins that stabilize the nodes extracellularly (48).…”

Heterophilic Interactions of Sodium Channel β1 Subunits with Axonal and Glial Cell Adhesion Molecules

“…In contrast, sodium channel ␤3 subunits do not appear to interact with ␤1. Nf155 and NrCAM are important for formation and maintenance of both CNS and PNS nodes of Ranvier (2,3,6). ␤2 is critical for sodium channel cell surface expression in vitro and in vivo (19,46,47).…”

“…The axo-glial complex in myelinated axons is composed of a nodal gap region that contains high density clusters of voltagegated sodium channels and a juxtaparanodal region that contains voltage-gated potassium channels (1)(2)(3)(4)(5)(6). The nodal gap and the juxtaparanode are separated by the paranode, a region containing septate-like junctions composed of cell adhesion molecules (CAMs) 1 that act as diffusion barriers to ion channel movement (2, 6 -8).…”