Nodes of Ranvier
Encyclopedia
Myelin sheath gaps or nodes of Ranvier are the gaps (approximately 1 micrometer
in length) formed between the myelin sheaths generated by different cells. A myelin sheath is a many-layered coating, largely composed of a fatty substance called myelin, that wraps around the axon
of a neuron
and very efficiently insulates it. At nodes of Ranvier, the axonal membrane is uninsulated and therefore capable of generating electrical activity.
sheath allowing rapid and efficient saltatory ("jumping") propagation
of action potential
s. 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
(CNS) and Schwann cells in the peripheral nervous system
(PNS), are wrapped around the axon, leaving the axolemma
relatively uncovered at 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 rolled up 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
steming from the outer aspect of the Schwann cell
membrane in the PNS, or by perinodal extensions from astrocytes in the CNS.
The myelin sheath of long nerves was discovered and named by German pathological
anatomist Rudolf Virchow
in 1854. French pathologist and anatomist Louis-Antoine Ranvier
later discovered the nodes, or gaps, in the myelin sheath that now bear his name. Born in Lyon
, Ranvier was one of the most prominent histologists
of the late 19th century and was the chairman of General Anatomy at the Collège de France
in 1875. His refined histological techniques and his work on both injured and normal nerve
fibers became world renowned. His observations on fiber nodes and the degeneration and regeneration of cut fibers had a great influence on Parisian neurology at the Salpêtrière
.
Ranvier abandoned pathological studies in 1867 and became an assistant of Claude Bernard
. Soon afterwards, he discovered gaps in sheaths of nerve fibers, in which was later called the Nodes of Ranvier. This discovery later led Ranvier to careful histological examination of myelin sheaths and Schwann cells.
segments that are referred to as internodes. 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 a couple millimeters more, 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.
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, Schwann cell
microvilli are replaced by astrocyte
perinodal extensions.
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.
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 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.
microvilli protein gliomedin as the likely binding partner of axonal neurofascin brings forward substantial evidence for the importance of this protein in recruiting Nav channels to the nodes of Ranvier. Furthermore, Lambert et al. and Eshed et al. also indicates that neurofascin accumulates before Nav channels and is likely to have crucial roles in the earliest events associated with node of Ranvier formation. Thus, multiple mechanisms may exist and work synergistically to facilitate clustering of Nav channels at nodes of Ranvier.
Septate-like junctions form at the paranodes with the enrichment of NF155 in glial paranodal loops. Immediately following the early differentiation of the nodal and paranodal regions, potassium channels, Caspr2 and TAG1 accumulate in the juxta-paranodal regions. This accumulation coincides directly with the formation of compact myelin
. In mature nodal regions, interactions with the intracellular proteins appear vital for the stability of all nodal regions. In the CNS, oligodendrocytes do not possess microvilli, but appear capable to initiate the clustering of some axonal proteins through secreted factors. The combined effects of such factors with the subsequent movements generated by the wrapping of oligodendrocyte
periaxonal extension could account for the organization of CNS nodes of Ranvier.
in myelinated axons requires organization of the nodes of Ranvier, whereas voltage-gated sodium channels are highly populated. Studies show that αII-Spectrin, a component of the cytoskeleton is enriched at the nodes and paranodes at early stages and as the nodes mature, the expression of this molecule disappears. It is also proven that αII-Spectrin in the axonal cytoskeleton is absolutely vital for stabilizing sodium channel clusters and organizing the mature node of Ranvier.
Evidence proves that OMgp accumulates in nodes of Ranvier of myelinated axons in the CNS, which supports the idea that OMgp is a nodal molecule. During the early stages of axonglial interaction, OMgp expression and clustering is related closely to the process of myelination. On the other hand, in de-myelinated animal models, OMgp distribution is ectopic and dispersed rather than clustered into the nodes of Ranvier. This observation suggests that the accumulation of OMgp in the nodes might depend on myelin
integrity and sub-cellular axonal polarization. OMgp is not detected in all nodes and undetectable in a subset of smaller axons. However, there seems to be a proportional relationship between the accumulation of OMgp and axon diameter. This indicates that a change in the concentration of OMgp may have a sever impact on a sub-population of axons.
is a spike of positive and negative ionic discharge that travels along the membrane of a cell. The creation and conduction of action potentials represents a fundamental means of communication in the nervous system. Action potentials represent rapid reversals in voltage across the plasma membrane of axons. These rapid reversals are mediated by voltage-gated ion channels found in the plasma membrane.
The action potential travels from one location in the cell to another, but ion flow across the membrane occurs only at the nodes of Ranvier. As a result, the action potential signal jumps along the axon, from node to node, rather than propagating smoothly, as they do in axons that lack a myelin sheath. The clustering of voltage-gated sodium and potassium ion channels at the nodes permits this behavior.
conduction for unmyelinated axons, and saltatory conduction
for myelinated axons. Saltatory conduction is defined as an action potential moving in discrete jumps down a myelinated axon.
This process is outlined as the charge passively spreading to the next node of Ranvier to depolarize it to threshold which will then trigger an action potential in this region which will then passively spread to the next node and so on.
Saltatory conduction provides two advantages over conduction that occurs along an axon without myelin sheaths. First, it saves energy by decreasing the use of sodium-potassium pumps in the axonal membrane. Secondly, the increased speed afforded by this mode of conduction assures faster interaction between neurones.
Micrometre
A micrometer , is by definition 1×10-6 of a meter .In plain English, it means one-millionth of a meter . Its unit symbol in the International System of Units is μm...
in length) formed between the myelin sheaths generated by different cells. A myelin sheath is a many-layered coating, largely composed of a fatty substance called myelin, that wraps around the axon
Axon
An axon is a long, slender projection of a nerve cell, or neuron, that conducts electrical impulses away from the neuron's cell body or soma....
of a neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
and very efficiently insulates it. At nodes of Ranvier, the axonal membrane is uninsulated and therefore capable of generating electrical activity.
Overview
Many vertebrate axons are surrounded by a myelinMyelin
Myelin is a dielectric material that forms a layer, the myelin sheath, usually around only the axon of a neuron. It is essential for the proper functioning of the nervous system. Myelin is an outgrowth of a type of glial cell. The production of the myelin sheath is called myelination...
sheath allowing rapid and efficient saltatory ("jumping") propagation
Saltatory conduction
Saltatory conduction is the propagation of action potentials along myelinated axons from one node of Ranvier to the next node, increasing the conduction velocity of action potentials without needing to increase the diameter of an axon.-Mechanism:Because the cytoplasm of the axon is electrically...
of action potential
Action potential
In physiology, an action potential is a short-lasting event in which the electrical membrane potential of a cell rapidly rises and falls, following a consistent trajectory. Action potentials occur in several types of animal cells, called excitable cells, which include neurons, muscle cells, and...
s. 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
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
(CNS) and Schwann cells in the peripheral nervous system
Peripheral nervous system
The peripheral nervous system consists of the nerves and ganglia outside of the brain and spinal cord. The main function of the PNS is to connect the central nervous system to the limbs and organs. Unlike the CNS, the PNS is not protected by the bone of spine and skull, or by the blood–brain...
(PNS), are wrapped around the axon, leaving the axolemma
Axolemma
The axolemma is the cell membrane surrounding an axon. It is responsible for maintaining the membrane potential of the neuron, and it contains ion channels through which ions can flow. When this occurs, the voltage inside the axon changes, and depolarization or hyperpolarization of the membrane can...
relatively uncovered at regularly spaced nodes of Ranvier.
The internodal glial membranes are fused to form compact myelin
Myelin
Myelin is a dielectric material that forms a layer, the myelin sheath, usually around only the axon of a neuron. It is essential for the proper functioning of the nervous system. Myelin is an outgrowth of a type of glial cell. The production of the myelin sheath is called myelination...
, whereas the cytoplasm-filled paranodal loops of myelinating cells are spirally rolled up 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
Internodal segment
An internodal segment is the portion of a nerve fiber between two Nodes of Ranvier. The neurolemma or primitive sheath is not interrupted at the nodes, but passes over them as a continuous membrane....
, and its outermost part that is in contact with paranodes is referred to as the juxtaparanodal region. The nodes are encapsulated by microvilli
Microvillus
Microvilli are microscopic cellular membrane protrusions that increase the surface area of cells, and are involved in a wide variety of functions, including absorption, secretion, cellular adhesion, and mechanotransduction....
steming from the outer aspect of the Schwann cell
Schwann cell
Schwann cells or neurolemmocytes are the principal glia of the peripheral nervous system . Glial cells function to support neurons and in the PNS, also include satellite cells, olfactory ensheathing cells, enteric glia and glia that reside at sensory nerve endings, such as the Pacinian corpuscle...
membrane in the PNS, or by perinodal extensions from astrocytes in the CNS.
History
Pathology
Pathology is the precise study and diagnosis of disease. The word pathology is from Ancient Greek , pathos, "feeling, suffering"; and , -logia, "the study of". Pathologization, to pathologize, refers to the process of defining a condition or behavior as pathological, e.g. pathological gambling....
anatomist Rudolf Virchow
Rudolf Virchow
Rudolph Carl Virchow was a German doctor, anthropologist, pathologist, prehistorian, biologist and politician, known for his advancement of public health...
in 1854. French pathologist and anatomist Louis-Antoine Ranvier
Louis-Antoine Ranvier
Louis-Antoine Ranvier was a French physician, pathologist, anatomist and histologist, who discovered nodes of Ranvier, regularly spaced constrictions of the myelin sheath, occurying at varying intervals along the length of a nerve fiber.Ranvier was born and studied medicine at Lyon, graduating in...
later discovered the nodes, or gaps, in the myelin sheath that now bear his name. Born in Lyon
Lyon
Lyon , is a city in east-central France in the Rhône-Alpes region, situated between Paris and Marseille. Lyon is located at from Paris, from Marseille, from Geneva, from Turin, and from Barcelona. The residents of the city are called Lyonnais....
, Ranvier was one of the most prominent histologists
Histology
Histology is the study of the microscopic anatomy of cells and tissues of plants and animals. It is performed by examining cells and tissues commonly by sectioning and staining; followed by examination under a light microscope or electron microscope...
of the late 19th century and was the chairman of General Anatomy at the Collège de France
Collège de France
The Collège de France is a higher education and research establishment located in Paris, France, in the 5th arrondissement, or Latin Quarter, across the street from the historical campus of La Sorbonne at the intersection of Rue Saint-Jacques and Rue des Écoles...
in 1875. His refined histological techniques and his work on both injured and normal nerve
Nerve
A peripheral nerve, or simply nerve, is an enclosed, cable-like bundle of peripheral axons . A nerve provides a common pathway for the electrochemical nerve impulses that are transmitted along each of the axons. Nerves are found only in the peripheral nervous system...
fibers became world renowned. His observations on fiber nodes and the degeneration and regeneration of cut fibers had a great influence on Parisian neurology at the Salpêtrière
Pitié-Salpêtrière Hospital
The Pitié-Salpêtrière Hospital is a teaching hospital located in Paris, France. Part of the Assistance publique - Hôpitaux de Paris, it is one of Europe's largest hospitals...
.
Ranvier abandoned pathological studies in 1867 and became an assistant of Claude Bernard
Claude Bernard
Claude Bernard was a French physiologist. He was the first to define the term milieu intérieur . Historian of science I. Bernard Cohen of Harvard University called Bernard "one of the greatest of all men of science"...
. Soon afterwards, he discovered gaps in sheaths of nerve fibers, in which was later called the Nodes of Ranvier. This discovery later led Ranvier to careful histological examination of myelin sheaths and Schwann cells.
Structure
The nodes are the gaps between myelinMyelin
Myelin is a dielectric material that forms a layer, the myelin sheath, usually around only the axon of a neuron. It is essential for the proper functioning of the nervous system. Myelin is an outgrowth of a type of glial cell. The production of the myelin sheath is called myelination...
segments that are referred to as internodes. 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 a couple millimeters more, 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
Myelin
Myelin is a dielectric material that forms a layer, the myelin sheath, usually around only the axon of a neuron. It is essential for the proper functioning of the nervous system. Myelin is an outgrowth of a type of glial cell. The production of the myelin sheath is called myelination...
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
Schwann cell
Schwann cells or neurolemmocytes are the principal glia of the peripheral nervous system . Glial cells function to support neurons and in the PNS, also include satellite cells, olfactory ensheathing cells, enteric glia and glia that reside at sensory nerve endings, such as the Pacinian corpuscle...
at the node, three distinctive segments are represented: the stereotypic internode
Internodal segment
An internodal segment is the portion of a nerve fiber between two Nodes of Ranvier. The neurolemma or primitive sheath is not interrupted at the nodes, but passes over them as a continuous membrane....
, the paranodal region, and the node itself. In the internodal region, the Schwann cell
Schwann cell
Schwann cells or neurolemmocytes are the principal glia of the peripheral nervous system . Glial cells function to support neurons and in the PNS, also include satellite cells, olfactory ensheathing cells, enteric glia and glia that reside at sensory nerve endings, such as the Pacinian corpuscle...
has an outer collar of cytoplasm, a compact myelin
Myelin
Myelin is a dielectric material that forms a layer, the myelin sheath, usually around only the axon of a neuron. It is essential for the proper functioning of the nervous system. Myelin is an outgrowth of a type of glial cell. The production of the myelin sheath is called myelination...
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.
Structural Differences between Nodes in the CNS and PNS
Although freeze fracture studies have revealed that the nodal axolemma in both the CNS and PNS is enriched in intra-membranous particles (IMPs) 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.Composition
The nodes of Ranvier contain Na+/K+ ATPases, Na+/Ca2+ exchangers and high density of voltage-gated Na+ 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 Na+ channels.Ankyrin
Ankyrin
Ankyrins are a family of adaptor proteins that mediate the attachment of integral membrane proteins to the spectrin-actin based membrane skeleton. Ankyrins have binding sites for the beta subunit of spectrin and at least 12 families of integral membrane proteins...
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
Schwann cell
Schwann cells or neurolemmocytes are the principal glia of the peripheral nervous system . Glial cells function to support neurons and in the PNS, also include satellite cells, olfactory ensheathing cells, enteric glia and glia that reside at sensory nerve endings, such as the Pacinian corpuscle...
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
HAPLN2
Hyaluronan and proteoglycan link protein 2 also known as brain link protein 1 is a protein that in humans is encoded by the HAPLN2 gene. HAPLN1 codes for a related link protein that is expressed in cartilage while Bral1 is expressed in brain.- Function :Bral1 interacts with versican and brevican...
, and proteoglycan NG2, as well as phosphacan and versican V2. At CNS nodes, the axonal proteins also include contactin; however, Schwann cell
Schwann cell
Schwann cells or neurolemmocytes are the principal glia of the peripheral nervous system . Glial cells function to support neurons and in the PNS, also include satellite cells, olfactory ensheathing cells, enteric glia and glia that reside at sensory nerve endings, such as the Pacinian corpuscle...
microvilli are replaced by astrocyte
Astrocyte
Astrocytes , also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord...
perinodal extensions.
Molecular Organization
The molecular organization of the nodes is specialized for their function in impulse propagation. The level of sodium channels in the node versus the internodeInternodal segment
An internodal segment is the portion of a nerve fiber between two Nodes of Ranvier. The neurolemma or primitive sheath is not interrupted at the nodes, but passes over them as a continuous membrane....
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
Spectrin
Spectrin is a cytoskeletal protein that lines the intracellular side of the plasma membrane of many cell types in pentagonal or hexagonal arrangements, forming a scaffolding and playing an important role in maintenance of plasma membrane integrity and cytoskeletal structure...
and ankyrin
Ankyrin
Ankyrins are a family of adaptor proteins that mediate the attachment of integral membrane proteins to the spectrin-actin based membrane skeleton. Ankyrins have binding sites for the beta subunit of spectrin and at least 12 families of integral membrane proteins...
. The high density of ankyrin
Ankyrin
Ankyrins are a family of adaptor proteins that mediate the attachment of integral membrane proteins to the spectrin-actin based membrane skeleton. Ankyrins have binding sites for the beta subunit of spectrin and at least 12 families of integral membrane proteins...
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
Ankyrin
Ankyrins are a family of adaptor proteins that mediate the attachment of integral membrane proteins to the spectrin-actin based membrane skeleton. Ankyrins have binding sites for the beta subunit of spectrin and at least 12 families of integral membrane proteins...
with extremely high affinity. All of these proteins, including ankyrin
Ankyrin
Ankyrins are a family of adaptor proteins that mediate the attachment of integral membrane proteins to the spectrin-actin based membrane skeleton. Ankyrins have binding sites for the beta subunit of spectrin and at least 12 families of integral membrane proteins...
, 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.
Myelination of Nerve Fibers
The complex changes that the Schwann cellSchwann cell
Schwann cells or neurolemmocytes are the principal glia of the peripheral nervous system . Glial cells function to support neurons and in the PNS, also include satellite cells, olfactory ensheathing cells, enteric glia and glia that reside at sensory nerve endings, such as the Pacinian corpuscle...
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
Schwann cell
Schwann cells or neurolemmocytes are the principal glia of the peripheral nervous system . Glial cells function to support neurons and in the PNS, also include satellite cells, olfactory ensheathing cells, enteric glia and glia that reside at sensory nerve endings, such as the Pacinian corpuscle...
. This process is sequenced by the in-folding of the Schwann cell
Schwann cell
Schwann cells or neurolemmocytes are the principal glia of the peripheral nervous system . Glial cells function to support neurons and in the PNS, also include satellite cells, olfactory ensheathing cells, enteric glia and glia that reside at sensory nerve endings, such as the Pacinian corpuscle...
surface so that a double membrane of the opposing faces of the in-folded Schwann cell
Schwann cell
Schwann cells or neurolemmocytes are the principal glia of the peripheral nervous system . Glial cells function to support neurons and in the PNS, also include satellite cells, olfactory ensheathing cells, enteric glia and glia that reside at sensory nerve endings, such as the Pacinian corpuscle...
surface is formed. This membrane stretches and spirally wraps itself over and over as the in-folding of the Schwann cell
Schwann cell
Schwann cells or neurolemmocytes are the principal glia of the peripheral nervous system . Glial cells function to support neurons and in the PNS, also include satellite cells, olfactory ensheathing cells, enteric glia and glia that reside at sensory nerve endings, such as the Pacinian corpuscle...
surface continues. As a result, the increase in the thickness of the extension of the myelin
Myelin
Myelin is a dielectric material that forms a layer, the myelin sheath, usually around only the axon of a neuron. It is essential for the proper functioning of the nervous system. Myelin is an outgrowth of a type of glial cell. The production of the myelin sheath is called myelination...
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
Myelin
Myelin is a dielectric material that forms a layer, the myelin sheath, usually around only the axon of a neuron. It is essential for the proper functioning of the nervous system. Myelin is an outgrowth of a type of glial cell. The production of the myelin sheath is called myelination...
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 directions of the lamellar overhang of the myelin
Myelin
Myelin is a dielectric material that forms a layer, the myelin sheath, usually around only the axon of a neuron. It is essential for the proper functioning of the nervous system. Myelin is an outgrowth of a type of glial cell. The production of the myelin sheath is called myelination...
endings are of opposite sense. This junction, adjacent of the Schwann cells, constitutes the region designated as the node of Ranvier.
Early Stages of Development
Researchers prove that in the developing CNS, Nav1.2 is initially expressed at all forming nodes Ranvier. Upon maturation, nodal Nav1.3 is down-regulated and replaced by Nav1.6. Naz1.2 is also expressed during PNS node formation, which suggests that the switching of Nav-channel subtypes is a general phenomenon in the CNS and PNS. In this same investigation, it was shown that Nav1.6 and Nav1.2 colocalize at many nodes of Ranvier during early myelination. This also led to the suggestion that early clusters of Nav1.2 and Nav1.6 channels are destined to later become nodes of Ranvier. Neurofascin is also reported to be one of the first proteins to accumulate at newly forming nodes of Ranvier. They are also found to provide the nucleation site for attachment of ankyrin G, Nav channels, and other proteins. The recent identification of the Schwann cellSchwann cell
Schwann cells or neurolemmocytes are the principal glia of the peripheral nervous system . Glial cells function to support neurons and in the PNS, also include satellite cells, olfactory ensheathing cells, enteric glia and glia that reside at sensory nerve endings, such as the Pacinian corpuscle...
microvilli protein gliomedin as the likely binding partner of axonal neurofascin brings forward substantial evidence for the importance of this protein in recruiting Nav channels to the nodes of Ranvier. Furthermore, Lambert et al. and Eshed et al. also indicates that neurofascin accumulates before Nav channels and is likely to have crucial roles in the earliest events associated with node of Ranvier formation. Thus, multiple mechanisms may exist and work synergistically to facilitate clustering of Nav channels at nodes of Ranvier.
Nodal Formation
The first event appears to be the accumulation of cell adhesion molecules such as NF186 or NrCAM. The intra-cellular regions of these cell-adhesion molecules interact with ankyrin G, which serves as an anchor for sodium channels. At the same time, the periaxonal extension of the glial cell wraps around the axon, giving rise to the paranodal regions. This movement along the axon contributes significantly to the overall formation of the nodes of Ranvier by permitting heminodes formed at the edges of neighboring glial cells to fuse into complete nodes.Septate-like junctions form at the paranodes with the enrichment of NF155 in glial paranodal loops. Immediately following the early differentiation of the nodal and paranodal regions, potassium channels, Caspr2 and TAG1 accumulate in the juxta-paranodal regions. This accumulation coincides directly with the formation of compact myelin
Myelin
Myelin is a dielectric material that forms a layer, the myelin sheath, usually around only the axon of a neuron. It is essential for the proper functioning of the nervous system. Myelin is an outgrowth of a type of glial cell. The production of the myelin sheath is called myelination...
. In mature nodal regions, interactions with the intracellular proteins appear vital for the stability of all nodal regions. In the CNS, oligodendrocytes do not possess microvilli, but appear capable to initiate the clustering of some axonal proteins through secreted factors. The combined effects of such factors with the subsequent movements generated by the wrapping of oligodendrocyte
Oligodendrocyte
Oligodendrocytes , or oligodendroglia , are a type of brain cell. They are a variety of neuroglia. Their main function is the insulation of axons in the central nervous system of some vertebrates...
periaxonal extension could account for the organization of CNS nodes of Ranvier.
Paranode Regulation via Mitochondria Accumulation
Mitochondria and other membranous organelles are normally enriched in the PNP region of peripheral myelinated axons, especially those large caliber axons. The actual physiological role of this accumulation and factors that regulate it are not understood; however, it is known that mitochondria are usually present in areas of the cell that expresses a high energy demand. In these same regions, they are also understood to contain growth cones, synaptic terminals, and sites of action potential initiation and regeneration, such as the nodes of Ranvier. In the synaptic terminals, mitochondria produce the ATP needed to mobilize vesicles for neurotransmission. In the nodes of Ranvier, mitochondria serve as an important role in impulse conduction by producing the ATP that is essential to maintain the activity of energy-demanding ion pumps. Supporting this fact, about five times more mitochondria are present in the PNP axoplasm of large peripheral axons than in the corresponding internodal regions of these fibers.Nodal Regulation via αII-Spectrin
Saltatory conductionSaltatory conduction
Saltatory conduction is the propagation of action potentials along myelinated axons from one node of Ranvier to the next node, increasing the conduction velocity of action potentials without needing to increase the diameter of an axon.-Mechanism:Because the cytoplasm of the axon is electrically...
in myelinated axons requires organization of the nodes of Ranvier, whereas voltage-gated sodium channels are highly populated. Studies show that αII-Spectrin, a component of the cytoskeleton is enriched at the nodes and paranodes at early stages and as the nodes mature, the expression of this molecule disappears. It is also proven that αII-Spectrin in the axonal cytoskeleton is absolutely vital for stabilizing sodium channel clusters and organizing the mature node of Ranvier.
Nodal Regulation via the Recognition Molecule OMgp
It has been identified in-vivo and in-vitro that nodal OMgp is derived from oligodendrocytes and/or similar cells. Furthermore, it has also been shown that OMgp clusters at nodes of Ranvier. The clustering of OMgp during postnatal development is associated with and is dependent upon myelination. OMgp appears to regulate sodium channel expression and electrophysiological functions of axons. It also regulates myelination and nodal formation at postnatal stages.Evidence proves that OMgp accumulates in nodes of Ranvier of myelinated axons in the CNS, which supports the idea that OMgp is a nodal molecule. During the early stages of axonglial interaction, OMgp expression and clustering is related closely to the process of myelination. On the other hand, in de-myelinated animal models, OMgp distribution is ectopic and dispersed rather than clustered into the nodes of Ranvier. This observation suggests that the accumulation of OMgp in the nodes might depend on myelin
Myelin
Myelin is a dielectric material that forms a layer, the myelin sheath, usually around only the axon of a neuron. It is essential for the proper functioning of the nervous system. Myelin is an outgrowth of a type of glial cell. The production of the myelin sheath is called myelination...
integrity and sub-cellular axonal polarization. OMgp is not detected in all nodes and undetectable in a subset of smaller axons. However, there seems to be a proportional relationship between the accumulation of OMgp and axon diameter. This indicates that a change in the concentration of OMgp may have a sever impact on a sub-population of axons.
Action Potential
An action potentialAction potential
In physiology, an action potential is a short-lasting event in which the electrical membrane potential of a cell rapidly rises and falls, following a consistent trajectory. Action potentials occur in several types of animal cells, called excitable cells, which include neurons, muscle cells, and...
is a spike of positive and negative ionic discharge that travels along the membrane of a cell. The creation and conduction of action potentials represents a fundamental means of communication in the nervous system. Action potentials represent rapid reversals in voltage across the plasma membrane of axons. These rapid reversals are mediated by voltage-gated ion channels found in the plasma membrane.
The action potential travels from one location in the cell to another, but ion flow across the membrane occurs only at the nodes of Ranvier. As a result, the action potential signal jumps along the axon, from node to node, rather than propagating smoothly, as they do in axons that lack a myelin sheath. The clustering of voltage-gated sodium and potassium ion channels at the nodes permits this behavior.
Saltatory Conduction
Since an axon can be unmyelinated or myelinated, the action potential has two methods to travel down the axon. These methods are referred to as action potentialAction potential
In physiology, an action potential is a short-lasting event in which the electrical membrane potential of a cell rapidly rises and falls, following a consistent trajectory. Action potentials occur in several types of animal cells, called excitable cells, which include neurons, muscle cells, and...
conduction for unmyelinated axons, and saltatory conduction
Saltatory conduction
Saltatory conduction is the propagation of action potentials along myelinated axons from one node of Ranvier to the next node, increasing the conduction velocity of action potentials without needing to increase the diameter of an axon.-Mechanism:Because the cytoplasm of the axon is electrically...
for myelinated axons. Saltatory conduction is defined as an action potential moving in discrete jumps down a myelinated axon.
This process is outlined as the charge passively spreading to the next node of Ranvier to depolarize it to threshold which will then trigger an action potential in this region which will then passively spread to the next node and so on.
Saltatory conduction provides two advantages over conduction that occurs along an axon without myelin sheaths. First, it saves energy by decreasing the use of sodium-potassium pumps in the axonal membrane. Secondly, the increased speed afforded by this mode of conduction assures faster interaction between neurones.
External links
- Cell Centered Database - Node of Ranvier - "PNS, nerve (LM, Medium)"