Paranodal Axoglial Junctions, an Essential Component in Axonal Homeostasis

Abstract

In vertebrates, a high density of voltage-gated Na⁺ channel at nodes of Ranvier and of voltage-gated K⁺ channel at juxtaparanodes is necessary for rapid propagation of action potential, that is, for saltatory conduction in myelinated axons. Myelin loops attach to the axonal membrane and form paranodal axoglial junctions (PNJs) at paranodes adjacent to nodes of Ranvier. There is growing evidence that the PNJs contribute to axonal homeostasis in addition to their roles as lateral fences that restrict the location of nodal axolemmal proteins for effective saltatory conduction. Perturbations of PNJs, as in specific PNJ protein knockouts as well as in myelin lipid deficient mice, result in internodal axonal alterations, even if their internodal myelin is preserved. Here we review studies showing that PNJs play crucial roles in the myelinated axonal homeostasis. The present evidence points to two functions in particular: 1) PNJs facilitate axonal transport of membranous organelles as well as cytoskeletal proteins; and 2) they regulate the axonal distribution of type 1 inositol 1,4,5-trisphosphate receptor (IP₃R1) in cerebellar Purkinje axons. Myelinated axonal homeostasis depends among others on the state of PNJs, and consequently, a better understanding of this dependency may contribute to the clarification of CNS disease mechanisms and the development of novel therapies.

Keywords: IP3R1; Purkinje; calcium; myelin; paranodal junction.

FIGURE 1

The schematic drawing shows junctional complexes between oligodendrocytes and axons in myelinated axons. The nodal axolemma with voltage-gated Na⁺ channels (Nav) has concentrations of neurofascin 186 (NF186) and neuronal cell adhesion molecule (NrCAM) belonging to the L1-family of CAMs at the node of Ranvier. The cytoplasmic region of axonal NF186 and NrCAM binds ankyrinG (AnkG), which anchors the nodal complex to βIV-spectrin and to the actin cytoskeleton. AnkG enables the clustering of Nav and Kv7.2/7.3 channels. Extracellular matrices such as Brevican, Versican (Vcan), and TenascinR (TenR) are surrounding the nodes. At the paranode, the cis-complex of Caspr and contactin interacts in trans with NF155 on the paranodal myelin loop. This complex is stabilized by protein 4.1B which co-localizes with AnkB, aII/bII-spectrin. At the juxtaparanode, Shaker-type voltage gated K+ channels Kv1.1/1.2 form clusters. A complex of contactin2 (also known as TAG-1) and Caspr2 is implicated in the formation of juxtaparanodes.