Myelin sheath, a multilamellar membrane present in Central Nervous System and Peripheral Nervous System . It acts as an insulator in order to minimize axonal current flow across the axonal membrane . Myelin wraps several time around axons in segments called Nodes of Ranvier, which are periodical interruptions in the myelin sheath. These segments allow the fast and salutatory nerve impulse movement .
In a non-excited axon, because the membrane is 100 times more permeable to K+ than to Na+, then there is much more tendency to diffuse Potassium (K+)out than to take Sodium (Na+). This leads to a net movement of positive charge out of the axon, produces a potential difference that is negative inside (-65 mV) .
The activation of Sodium-Potassium channels is required for the maintenance of concentration gradients in axons . The giant axon of squid is 1 mm. This axon is not wrapped around myelin. So this big-diameter axon facilitates the propagation of axonal current, called as action potential, within it. Hence, if the Sodium pump in this axon is blocked, then thousands of action potentials can still get propagated, because Na+ and K+ can still cross the membrane. In the more sophisticated animals that have axons less than 1 µm diameter, the Sodium and Potassium fluxes within axons are very significant .
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Axons fall into two categories: The first group, named unmyelinated axons, are mainly all invertebrate axons that are loosely surrounded by a glial cell. The speed of action potential in these axons is proportional to the square root of the axon diameter. That is why in invertebrates such as squid, the axons are big in diameter .
The second category is the myelinated axons which include the vertebrate axons larger than 1 µm. They are tightly wrapped around several layers of myelin which are generated by glial cells . Through this structure of myelin, action potential travels rapidly within axon with little loss through nodes of Ranvier, where the current is boosted or regenerated . This regeneration is done by voltage-gated Sodium channels that are concentrated at the nodes . In fact, the nodes have specific structures that force the special placement of Sodium and Potassium channels within axons membrane . Sodium channels are present in nodal regions, while Potassium channels are within the juxtaparanodes which are the areas covered by myelin .
This feature is crucial for the proper flow of action potential in axons, while the deficient activity of neurons is observed in multiple neurodegenerative disorders caused by demyelination which loss of myelin sheath and incorrect structure of nodes of Ranvier bring about very gross abnormalities in both CNS and PNS .
Nodal region structure
Nodal regions share many structural similarities in CNS and PNS
As mentioned, Na+are essential for action potential, which are present in the area of nodes in high concentration . Nodal regions in CNS and PNS mostly contain Nav1.6 . While Kv3.1 and Kcnq2 are the predominant potassium channels at the nodes. Besides, there are several cell adhesion molecules in nodes. The most prominent of them include Nrcam, ankyrin G and spectrin βIV. Na+ channel β-subunits are important in delivery of Na+ channels to the cell surface. These channels are anchored to axolemma by ankyrin G. Ankyrin G also binds Nf186, Nrcam, and Kv3.1b. Ankyrin binds these proteins to axonal cytoskeleton by the actin binding protein spectrin βIV .
At the paranodes, which is the region just next to the nodes, contactin and Caspr (contactin-associated protein, a transmembrane protein) in axolemma interact with Nf155 at the glial loops. At this region, contctin, which is a glycosylphosphotidylinositol (GPI) anchored glycoprotein can bind Nf 155, while Caspr inhibits it. Concisely, contactin forms a complex with Capsr, and Nf155 serves as a glial ligand of Casr/contactin complex . Paranodes contain several loops, and each paranode loop represents a turn of myelin wrap. Each loop is tightly attached to the axolemma. There are gaps of approximately 2.5-3 nm between each membrane of the loops including the extracellular spaces which are interconnected with the cytoskeleton of glial loops and axons . Axoglial septate junction acts as a fense for inhibition of movement of K+ channels from beneath the myelin sheath to the nodes. In paranodes the two important molecules whose presence is crucial for axoglial junction are: Caspr and contactin. Caspr leads to cell adhesion and intracellular communication. They bind to Cell Adhesion Molecules (CAMs), and that is the reason they are called CAM associated proteins . Caspr/contactin complex binds the paranodal loops. Therefore, Deficiency in this complex increases the space between axon and paranodal loops. An obvious example of this defect is the abnormal distribution of Caspr in Multiple Sclerosis .
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Paranodal septate junction inhibits the movement of K+ channels from the axonal region which is under the compact myelin- juxtaparanode- to the nodes, while it does not have much effect on the distribution of the nodal Na+. At the juxtaparanode, which is next to paranodes, K+ channels make complex with Caspr2, Tag1, Psd 95 and protein 4.1 B. Transient axonal glycoprotein-1 (Tag1) is the molecule which is expressed in the membrane of glial cells and binds the axonal Caspr2/Tag1 complex . The complex of Caspr2/Tag1 in jucstaparanode is necessary for the accumulation of K+ channels in this area .
Nodal areas within PNS and CNS also have crucial differences
Although as mentioned, nodes and surrounding areas in CNS and PNS have many similarities within their structure, they could be distinguished by some other features. PNS myelin is covered by basal lamina which is the extension of the outer layer of Schwann cells. In this area, paranode contains microvilli as well as filamentous matrix. Schwann cell microvilli express ERM (ezrin-radixin-moesin) and DG (Dystroglycan) which are present in the nodal gap of PNS. Opposite to PNS, CNS myelin does not have basal lamina, and the contact between nodes is done by astrocytes . In the nodal gap of CNS, there are several proteoglycans and extracellular matrix proteins such as tenascin and phosphacan. It also has versican binding protein Bral1 . Besides, there are also different voltage-gated channels in CNS and PNS nodal areas. Nav1.2 and Nav1.8 are mostly found in many CNS nodes, while Nav1.9 is in some PNS nodes . Also, Kv3.1 is mainly present in large axons of CNS . In addition to all these, disruption of molecular structure of nodes in CNS and PNS has different features. For instance, the mutation of Caspr and contactin in the PNS is much milder than the CNS, because of the presence of the basal lamina in PNS .
Molecular assembly is also done within some several steps. Firstly, Na+ channels get clustered at the nodes form. Clustering of Na+ channels takes place just next to the processes of oligodendrocytes in CNS and Schwann cells in PNS. The longitudinal growth of these processes displaces these Na+ channel clusters, until they seem to fuse . Then, paranodal junctions generate. Later, K+ channels cluster at the juxtaparanodes .
In PNS, first Nrcam and Nf186, then ankyrin G and Na+ channels form; while in CNS first ankyrin G appears and then Nf186 and Na+ channels cluster. After clustering of nodal components, Nf155 and Caspr/contactin complex cluster in paranodes. Then Caspr2 and K+ channels cluster in the juxtaparanodes . In the process of myelination, K+ channels are firstly present in paranodes, but then interaction between Caspr2 and Tag1 relocates these channels to juxtaparanodes . During this development, myelin sheath firstly covers Na+ channels and Ig-CAMs; then these are excluded from the edges of myelinating glia, they allow the passage of K+ channels .
Nodes of Ranvier with their specific structure are the fundamental features in axons that boost action potential speed. K+ channels maintain the resting potential and mediate the axonal communication, while Na+ are necessary for the start of action potential at the stimulated site . When a neuron is excited, the voltage-gated Na+ and K+ channels respond, that will lead to the generation and propagation of action potential. The generated action potential skips down the myelinated area which produces salutatory conduction. In these areas, nodes of Ranvier act as boosters to ensure the transmission of this action potential to the next node . There have been a lot of studies about action potential, boosters and inhibitors, and different factors prominent in their generation and flow. The first study on axonal membrane current was done by Hodgkin and Huxly that was done on squid giant axon. The first report of recording action potential in human node of Ranvier was done by Schwarz et al, which showed that there are much similarity between the construction of human nodes of Ranvier and those in rat and rabbit; while there are also very minute differences, such as larger Na+ permeability at human than rat nodes . Although such studies are groundbreaking, but should be studied a lot more. We should consider that there are many demyelination disorders such as Multiple Sclerosis that are not curable, yet. Although in these diseases, demyelination solely is not the reason of the disorder, but it is one of the main factors. Better knowledge of human nodal and myelin structure, and their differences with their counterparts in other studied animal models can help us in genetic manipulations and even over/down regulation of the genes pivotal in the nodal and myelin structure. This could lead to the cure of many neuronal diseases.
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