Organization of nodes of Ranvier

The myelin sheath, produced by oligodendrocytes and Schwann cells, divides the axon into myelinated internodal segments, the length of which may vary between 100 ^m for small axons to ~1 mm for large-diameter fibres. The internodal segments are separated by nonmyelinated regions, known as nodes of Ranvier (Figure 8.10). The myelin, being a perfect isolator, therefore divides the membrane

Saltatory Conduction Myelinated

Figure 8.10 The node of Ranvier. Saltatory conduction, whereby action potentials jump from node to node, is dependent on the myelin sheath, because of both its insulating properties and its separation of sodium and potassium channels at nodes of Ranvier. The voltage-gated Na+ channels that generate the upshoot of the action potential are clustered in the nodal axolemma. The voltage-gated K+ channels that are responsible for repolarization of the action potential are localized to the juxtaparanodal region. The complex axoglial junctions between the myelin sheath paranodal loops and axolemma separate the two groups of ion channels, and disruption of these junctions dampens action potential propagation

Figure 8.10 The node of Ranvier. Saltatory conduction, whereby action potentials jump from node to node, is dependent on the myelin sheath, because of both its insulating properties and its separation of sodium and potassium channels at nodes of Ranvier. The voltage-gated Na+ channels that generate the upshoot of the action potential are clustered in the nodal axolemma. The voltage-gated K+ channels that are responsible for repolarization of the action potential are localized to the juxtaparanodal region. The complex axoglial junctions between the myelin sheath paranodal loops and axolemma separate the two groups of ion channels, and disruption of these junctions dampens action potential propagation of nerve fibre into alternating conductive and nonconductive portions. Because of this, the action potential in myelinated axons is shunted from node to node through a low-resistance axoplasm. This propagation is highly reliable (which is achieved by a specific clustering of ion channels, see below) and the safety factor (which is determined as a ratio between the current generated in the node and the current required to stimulate the node) is as big as 5-8. The speed of action potential jumping between the nodes is determined by an internodal conduction time, which at 37 °C is around 20 ^s (or 0.00002 s). The propagation of action potentials through myelinated axons is unidirectional, as the inactivation state of sodium channels (which is induced by depolarization and follows the open state) lasts longer than the internodal conduction time.

The plasma membrane of myelinated axons shows a very specific distribution of voltage-gated channels, which provides a molecular basis for saltatory conduction of action potentials along the nerve fibre. The voltage-gated Na+ channels, which generate the initial phase of the action potential, are clustered in the nodal membrane at a very high density (>1000 channels/^m2); in contrast their density in the internodal regions falls sharply to ~20-25 channels per ^m2 (Figure 8.10). Molecularly, the nodal membrane predominantly contains voltage-gated channels of Nav1.6 type (overall 9 sodium channels, Nav1.1 to Nav1.9 have been cloned to date), which are classical very rapid, tetrodotoxin(TTX)-sensitive channels. Small quantities of other sodium channel types (Nav1.2 and TTX-resistant Nav1.8) have also been detected within the nodal membranes. In contrast, the membranes of nonmyelinated thin nociceptive fibres may contain higher densities of Nav1.8 channels and also Nav1.9 channels, which are resistant to TTX and do not inactivate upon depolarization.

The membrane of myelinated axons also contains several types of potassium channels, responsible for repolarization of the action potential. These are represented by fast A-type K+ channels, which control initial rapid repolarization; slow outwardly rectifying K+ channels, which are responsible for final repolarization; and inwardly rectifying channels, which set the resting potential level. The density of fast K+ channels is the highest in the juxtaparanodal region under the myelin sheath (Figure 8.10), and it is several times lower in the membrane of the node and in the internodal membrane. This particular distribution of K+ channels assists in localizing the action potential to the nodal region. The specific distribution of K+ channels is relevant to neuronal pathology associated with demyelination, as destruction of the myelin sheath exposes all the K+ channels, which very effectively dampens action potential propagation through parts of the axon that lost myelin.

Accumulation of voltage-gated sodium channels at the nodes of Ranvier is a prerequisite for saltatory conduction. Clustering is dependent on myelinating Schwann cells and oligodendrocytes, involving the developmental organization of the neighbouring paranodes and juxtaparanodes (Figure 8.11). Molecular components of the nodal, paranodal, and juxtaparanodal zones include cell adhesion molecules and cell-surface molecules involved in cell-cell interactions. The paranodal junction comprises the axon proteins Caspr (paranodin) and contactin,

Juxtaparanodal Zones

Figure 8.11 Myelinating cells and induction of nodes of Ranvier. Sodium channel clustering at nodes of Ranvier is dependent on the myelinating cells in both the PNS and CNS. Studies during development and following remyelination of demyelinated axons indicate differences between Schwann cells and oligodendrocytes. In the PNS, the clustering of Na+ channels is dependent on contact by the myelinating Schwann cell; Na+ channel clusters form at the 'terminals' of the immature myelin sheath and are 'shepherded' along the axolemma as the myelin sheath grows, to combine with consecutive clusters to establish the node of Ranvier. In the CNS, Na+ channels cluster at presumptive nodes of Ranvier in response to diffusible and contact-mediated signals from oligodendrocytes; subsequently, myelin sheaths grow to 'fill in' the internodal region, and late developing oligodendrocytes fill in any unmyelinated spaces. These models are based on experimental observations, but they leave many questions unanswered. For example, the glia-to-axon and axon-to-glia signals are unknown. Furthermore, it is not clear how the strict relationship between nodal periodicity and axon diameter is established during development; both depend on myelination, but the mechanisms are unknown

Figure 8.11 Myelinating cells and induction of nodes of Ranvier. Sodium channel clustering at nodes of Ranvier is dependent on the myelinating cells in both the PNS and CNS. Studies during development and following remyelination of demyelinated axons indicate differences between Schwann cells and oligodendrocytes. In the PNS, the clustering of Na+ channels is dependent on contact by the myelinating Schwann cell; Na+ channel clusters form at the 'terminals' of the immature myelin sheath and are 'shepherded' along the axolemma as the myelin sheath grows, to combine with consecutive clusters to establish the node of Ranvier. In the CNS, Na+ channels cluster at presumptive nodes of Ranvier in response to diffusible and contact-mediated signals from oligodendrocytes; subsequently, myelin sheaths grow to 'fill in' the internodal region, and late developing oligodendrocytes fill in any unmyelinated spaces. These models are based on experimental observations, but they leave many questions unanswered. For example, the glia-to-axon and axon-to-glia signals are unknown. Furthermore, it is not clear how the strict relationship between nodal periodicity and axon diameter is established during development; both depend on myelination, but the mechanisms are unknown and their probable glial partner is neurofascin 155 (NF155). The developmental appearance of these molecules at paranodes coincides with the appearance of constituents of the node, including NF186, ankyrin G, NrCAM and PIV spectrin, closely followed by voltage-gated sodium channels.

Ensheathment and node formation are interrelated events. The first event triggered by the myelinating cells is the clustering of axonal adhesion proteins, such as NrCAM and NF186. In PNS, this requires direct cell-cell contact by Schwann cells, whereas clustering in the CNS is triggered in response to a soluble factor from oligodendrocytes (but also requires contact mediated signals). Recruitment of ankyrin G is required for the clustering of Na+ channels, and the stability of these clusters is dependent on NrCAM and NF186, and PIV spectrin. As the myelin sheath becomes compacted, the lateral cytoplasmic ridges stack upon each other to form the paranodal region. At this time Caspr/paranodin-contactin complexes in the axolemma interact with NF155 in the glial membrane to form septate-like junctions. Intracellular junctions between the paranodal loops involve connexins. The paranodal junctions anchor the glial cell membrane to the axolemma, and serve as barriers for stopping the apparent movement of juxtaparanodal components. The precise mechanism of the juxtaparanodal accumulation of K+ channels remains to be determined, but involves Caspr2 and TAG1. The two isoforms of neurofascin (NF), NF155 in glia and NF186 in neurones, are required for the assembly of the specialized nodal and paranodal domains. In NF knockout mice, neither paranodal adhesion junctions nor nodal complexes are formed.

In the PNS, dystroglycan is crucial for nodal architecture, possibly by mediating interactions between Schwann cell microvilli and the nodal axolemma. Gliomedin is a glial ligand for neuronal NF and NrCAM in the PNS. Gliomedin is expressed by myelinating Schwann cells and accumulates at the edges of each myelin segment during development, where it aligns with the forming nodes. Disruption of gliomedin expression abolishes node formation. The impact of myelinating Schwann cells on the molecular architecture of the node of Ranvier is demonstrated in mice deficient in P0. Abnormal myelin formation and compaction results in disruption of nodal sodium channel clustering, with ectopic nodal expression of the Nav1.8 isoform, where it is coexpressed with the ubiquitous Nav1.6 channel. Caspr is distributed asymmetrically or is even absent in the mutant nerve fibres, and the potassium channel Kv1.2 and Caspr2 are not confined to juxtaparanodes, but often protrude into the paranodes.

PART III

Glia and Nervous System Pathology

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Responses

  • Lois Reilly
    Is schwann cells sparated by nodes of ranvier?
    5 years ago
  • Brigitte
    Are voltagegated channels prevalent at myelin sheath?
    7 months ago

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