Node of Ranvier
Nodes of Ranvier, also known as myelin-sheath gaps, occur along a myelinated axon where the axolemma is exposed to the extracellular space. Nodes of Ranvier are uninsulated axonal domains that are high in sodium and potassium ion channels complexed with cell adhesion molecules, allowing them to participate in the exchange of ions required to regenerate the action potential. Nerve conduction in myelinated axons is referred to as saltatory conduction due to the manner in which the action potential seems to "jump" from one node to the next along the axon. This results in faster conduction of the action potential. The nodes of Ranvier are present in both the peripheral and central nervous systems.
Overview
The nodes are primarily composed of sodium and potassium voltage-gated ion channels; CAMs such as neurofascin-186 and NrCAM; and cytoskeletal adaptor proteins such as ankyrin-G and spectrinβIV.Many vertebrate axons are surrounded by a myelin sheath, allowing rapid and efficient saltatory propagation of action potentials. The contacts between neurons and glial cells display a very high level of spatial and temporal organization in myelinated fibers. The myelinating glial cells - oligodendrocytes in the central nervous system, and Schwann cells in the peripheral nervous system - are wrapped around the axon, leaving the axolemma relatively uncovered at the regularly spaced nodes of Ranvier.
The internodal glial membranes are fused to form compact myelin, whereas the cytoplasm-filled paranodal loops of myelinating cells are spirally wrapped around the axon at both sides of the nodes. This organization demands a tight developmental control and the formation of a variety of specialized zones of contact between different areas of the myelinating cell membrane. Each node of Ranvier is flanked by paranodal regions where helicoidally wrapped glial loops are attached to the axonal membrane by a septate-like junction.
The segment between nodes of Ranvier is termed as the internode, and its outermost part that is in contact with paranodes is referred to as the juxtaparanodal region. The nodes are encapsulated by microvilli stemming from the outer aspect of the Schwann cell membrane in the PNS, or by perinodal extensions from astrocytes in the CNS.
Structure
The internodes are the myelin segments and the gaps between are referred to as nodes. The size and the spacing of the internodes vary with the fiber diameter in a curvilinear relationship that is optimized for maximal conduction velocity. The size of the nodes span from 1–2 μm whereas the internodes can be up to 1.5 millimetres long, depending on the axon diameter and fiber type.The structure of the node and the flanking paranodal regions are distinct from the internodes under the compact myelin sheath, but are very similar in CNS and PNS. The axon is exposed to the extra-cellular environment at the node and is constricted in its diameter. The decreased axon size reflects a higher packing density of neurofilaments in this region, which are less heavily phosphorylated and are transported more slowly. Vesicles and other organelles are also increased at the nodes, which suggest that there is a bottleneck of axonal transport in both directions as well as local axonal-glial signaling.
When a longitudinal section is made through a myelinating Schwann cell at the node, three distinctive segments are represented: the stereotypic internode, the paranodal region, and the node itself. In the internodal region, the Schwann cell has an outer collar of cytoplasm, a compact myelin sheath, and inner collar of cytoplasm, and the axolemma. At the paranodal regions, the paranodal cytoplasm loops contact thickenings of the axolemma to form septate –like junctions. In the node alone, the axolemma is contacted by several Schwann microvilli and contains a dense cytoskeletal undercoating.
Differences in the central and peripheral nervous systems
Although freeze fracture studies have revealed that the nodal axolemma in both the CNS and PNS is enriched in intra-membranous particles compared to the internode, there are some structural differences reflecting their cellular constituents. In the PNS, specialized microvilli project from the outer collar of Schwann cells and come very close to nodal axolemma of large fibers. The projections of the Schwann cells are perpendicular to the node and are radiating from the central axons. However, in the CNS, one or more of the astrocytic processes come in close vicinity of the nodes. Researchers declare that these processes stem from multi-functional astrocytes, as opposed to from a population of astrocytes dedicated to contacting the node. On the other hand, in the PNS, the basal lamina that surrounds the Schwann cells is continuous across the node. A study suggests that in the CNS, nerve cells individually alter the size of the nodes to tune conduction speeds, leading node length to vary much more across different axons than within one.Composition
The nodes of Ranvier exchangers and high density of voltage-gated channels that generate action potentials. A sodium channel consists of a pore-forming α subunit and two accessory β subunits, which anchor the channel to extra-cellular and intra-cellular components. The nodes of Ranvier in the central and peripheral nervous systems mostly consist of αNaV1.6 and β1 subunits. The extra-cellular region of β subunits can associate with itself and other proteins, such as tenascin R and the cell-adhesion molecules neurofascin and contactin. Contactin is also present at nodes in the CNS and interaction with this molecule enhances the surface expression of channels.Ankyrin has been found to be bounded to βIV spectrin, a spectrin isoform enriched at nodes of Ranvier and axon initial segments. The PNS nodes are surrounded by Schwann cell microvilli, which contain ERMs and EBP50 that may provide a connection to actin microfilaments. Several extracellular matrix proteins are enriched at nodes of Ranvier, including tenascin-R, Bral-1, and proteoglycan NG2, as well as phosphacan and versican V2. At CNS nodes, the axonal proteins also include contactin; however, different from the PNS, Schwann cell microvilli are replaced by astrocyte perinodal extensions.
Molecular organization
The molecular organization of the nodes corresponds to their specialized function in impulse propagation. The level of sodium channels in the node versus the internode suggests that the number IMPs corresponds to sodium channels. Potassium channels are essentially absent in the nodal axolemma, whereas they are highly concentrated in the paranodal axolemma and Schwann cell membranes at the node. The exact function of potassium channels have not quite been revealed, but it is known that they may contribute to the rapid repolarization of the action potentials or play a vital role in buffering the potassium ions at the nodes. This highly asymmetric distribution of voltage-gated sodium and potassium channels is in striking contrast to their diffuse distribution in unmyelinated fibers.The filamentous network subjacent to the nodal membrane contains cytoskeletal proteins called spectrin and ankyrin. The high density of ankyrin at the nodes may be functionally significant because several of the proteins that are populated at the nodes share the ability to bind to ankyrin with extremely high affinity. All of these proteins, including ankyrin, are enriched in the initial segment of axons which suggests a functional relationship. Now the relationship of these molecular components to the clustering of sodium channels at the nodes is still not known. Although some cell-adhesion molecules have been reported to be present at the nodes inconsistently; however, a variety of other molecules are known to be highly populated at the glial membranes of the paranodal regions where they contribute to its organization and structural integrity.
Development
Myelination of nerve fibers
The complex changes that the Schwann cell undergoes during the process of myelination of peripheral nerve fibers have been observed and studied by many. The initial envelopment of the axon occurs without interruption along the entire extent of the Schwann cell. This process is sequenced by the in-folding of the Schwann cell surface so that a double membrane of the opposing faces of the in-folded Schwann cell surface is formed. This membrane stretches and spirally wraps itself over and over as the in-folding of the Schwann cell surface continues. As a result, the increase in the thickness of the extension of the myelin sheath in its cross-sectional diameter is easily ascertained. It is also evident that each of the consecutive turns of the spiral increases in size along the length of the axon as the number of turns increase. However, it is not clear whether or not the increase in length of the myelin sheath can be accounted solely by the increase in length of axon covered by each successive turn of the spiral, as previously explained.At the junction of two Schwann cells along an axon, the directions of the lamellar overhang of the myelin endings are of opposite sense. This junction, adjacent of the Schwann cells, constitutes the region designated as the node of Ranvier.