Satellite cells (glial)
Encyclopedia
Satellite glial cells are a type of glial cell
that line the exterior surface of neurons in the peripheral nervous system
(PNS). Satellite glial cells (SGCs) also surround neuron cell bodies within ganglia. They are of a similar embryological origin to Schwann cells of the PNS, as they are both derived from the neural crest
of the embryo during development. SGCs have been found to hold a variety of roles, including control over the microenvironment of sympathetic ganglia. They are thought to have a similar role to astrocytes in the central nervous system
(CNS). They supply nutrients to the surrounding neurons and also have some structural function. Satellite cells also act as protective, cushioning cells. Additionally, they express a variety of receptors that allow for a range of interactions with neuroactive chemicals. Many of these receptors and other ion channels have recently been implicated in health issues including chronic pain
and herpes simplex
. There is much more to be learned about these cells, and research surrounding additional properties and roles of the SGCs is ongoing.
Satellite glial cells are the principle glial cells found in the peripheral nervous system, specifically in sensory
, sympathetic, and parasympathetic ganglia. They compose the thin cellular sheaths that surround the individual neurons in these ganglia.
In an SGC, the cell body is denoted by the region containing the single, relatively large nucleus
. Each side of the cell body extends outward, forming perineuronal processes. The region containing the nucleus has the largest volume of cytoplasm
, making this region of the SGC sheath thicker. The sheath can be even thicker if multiple SGCs are layered on top of one another, each measuring 0.1 μm.
Despite their flattened shape, satellite glial cells contain all common organelles necessary to make cellular products and to maintain the homeostatic environment of the cell. The plasma membrane
of SGCs is thin and not very dense, and it is associated with adhesion molecules, receptors for neurotransmitter
s and other molecules, and ion channel
s, specifically potassium ion channels. Within individual SGCs, there is both rough endoplasmic reticulum
and smooth endoplasmic reticulum, but the latter is much less abundant. Most often the Golgi apparatus
and the centriole
s in an SGC are found in a region very close to the cell’s nucleus. On the other hand, mitochondria
are found throughout the cytoplasm along with the organelles involved in autophagy
and other forms of catabolic degradation, such as lysosome
s, lipofuscin
granules, and peroxisome
s. Both microtubule
s and intermediate filament
s can be seen throughout the cytoplasm, and most often they lie parallel to the SGC sheath. These filaments are found in greater concentrations at the axon hillock
and at the beginning portion of an axon
in an SGC of the sympathetic ganglia. In some SGCs of the sensory ganglia researchers have seen a single cilium
that extends outward from the cell surface near the nucleus and into the extracellular space of a deep indentation in the plasma membrane. The cilium, however, only has the nine pairs of peripheral microtubules while it lacks the axial pair of microtubules, making its structure very similar to the cilia of neurons, Schwann cells, and astrocytes of the CNS.
ta. The distance of extracellular space between the sheath and the neuronal plasma membrane measures 20 nanometre (7.8740157480315E-07 in), allowing the neuron and its SGC sheath to form a single anatomical and functional unit. These individual units are separated by areas of connective tissue. However, there are some sensory neurons that occupy the same space within connective tissue and are therefore grouped together in a “cluster” of two or three neurons. Most often each individual neuron in a cluster is still surrounded by its own SGC sheath, but in some cases it is missing. Some sensory neurons have small projections called microvilli that extend outward from their cell surfaces. Due to their close proximity to the SGC sheath, these microvilli of the neuronal plasma membrane reach into the grooves of the sheath, allowing for possible exchange of materials between the cells.
. SIF cells of sympathetic ganglia are separated into groups, each of which is surrounded by an SGC sheath. The SGCs of the sympathetic ganglia come from the neural crest and do not proliferate during embryonic development until the neurons are present and mature, indicating that the neurons signal the division and maturation of the SGCs. The SGCs of sympathetic ganglia follow the same basic structure as the SGCs of sensory ganglia, except that sympathetic ganglia also receive synapse
s. Therefore, the SGC sheath of sympathetic neurons must extend even further to cover the axon hillock near the somata. Like the regions of the sheath near the glial nucleus, the regions of the sheath at the axon hillocks are thicker than those surrounding the rest of the neuron. This indicates that the SGCs play a role in the synaptic environment, thereby influencing synaptic transmission.
. However, there are distinguishing factors that put SGCs in their own distinct category of glial cells. SGCs most often surround individual sensory and parasympathetic neurons with a complete, unbroken sheath while most neurons of sympathetic ganglia lack a completely continuous SGC sheath, allowing for limited direct exchange of materials between the extracellular space of the neuron and the space within the connective tissue
where the SGCs are situated. Furthermore, gap junction
s exist between SGCs in the sheaths of adjacent neurons as well as between SGCs in the same sheath (reflexive gap junctions). These gap junctions have been identified through the use of electron microscopy
and weight tracer markers, such as Lucifer yellow
or neurobiotin. The degree to which SGCs are coupled to SGCs of another sheath or to SGCs of the same sheath is dependent on the pH
of the cellular environment.
From studies on rats and mice, researchers have found that satellite glial cells express many neurotransmitter receptors, such as muscarinic acetylcholine and erythropoietin
receptors. In order to differentiate between SGCs and other glial cells researchers have used markers to identify which proteins are found in different cells. Although SGCs express glial fibrillary acidic protein
(GFAP)and different S-100 protein
s, the most useful marker available today for SGC identification is glutamine synthetase
(GS). The levels of GS are relatively low at rest, but they greatly increase if the neuron undergoes axonal damage. Furthermore, SGCs also possess mechanisms to release cytokine
s, adenosine triphosphate
(ATP), and other chemical messengers.
, they are not found on the neuron surface. This suggests that the SGCs can regulate the extracellular space of individual neurons. Some speculate that SGCs in the autonomic ganglia have a similar role to the blood-brain barrier
as a functional barrier to large molecules.
SGCs role as a regulator of neuronal microenvironment is further characterized by its electrical properties which are very similar to that of astrocytes. Astrocytes have a well studied and defined role in controlling the microenvironment within the brain
, therefore researchers are investigating any homologous role of SGCs within the sympathetic ganglia. An established mode of controlling the microenvironment in sensory ganglia is the uptake of substances by specialized transporters which carry neurotransmitters into cells when coupled with Na+ and Cl−. Transporters for glutamate and gamma-Aminobutyric acid
(GABA) have been found in SGCs. They appear to be actively engaged in the control of the composition of the extracellular space of the ganglia. The enzyme glutamine synthetase, which catalyzes the conversion of glutamate into glutamine, is found in large amounts in SGCs. Additionally, SGCs contain the glutamate related enzymes glutamate dehydrogenase
and pyruvate carboxylase
, and thus can supply the neurons not only with glutamine, but also with malate
and lactate
.
(ACh), GABA, glutamate, ATP, noradrenaline, substance P
, and capsaicin
that directly affect the physiology of these cells. Current research is revealing that SGCs are also able to respond to some of the same chemical stimuli as neurons. The research is ongoing and SGCs role in injury repair mechanisms is not yet fully understood.
and other forms of spontaneous pain.
because of some of their physiological and pharmacological properties. In fact, just like astrocytes, SGCs have the ability to sense and regulate neighboring neuronal activity. First, after a period of nerve cell injury, SGCs are known to up-regulate GFAP and to undergo cell division. They have the ability to release chemoattractants
, which are analogous to those released by Schwann cells and contribute to the recruitment and proliferation of macrophages. Additionally, several research groups have found that SGC coupling increases after nerve damage, which has an effect on the perception of pain, likely for several reasons. Normally, the gap junctions between SGCs are used in order to redistribute potassium ions between adjacent cells. However, in coupling of SGCs, the number of gap junctions greatly increases. This may possibly be to deal with larger amounts of ATP and glutamate, which eventually leads to increased recycling of the glutamate. The increased levels of glutamate lead to over excitation and an increase in nociception.
from macrophages or microglia and astrocytes. The receptor likely has a part in the cascade of events that end with inflammation and neuropathic pain. It has been discovered that this receptor has an antagonist in the form of A-317491, which, when present, has the ability to reduce both the evoked and unprompted firing of various classes of spinal neurons, as well as to inhibit release of IL-1β. However, the outside influences of receptors P2X3 and P2Y1
are believed to complicate the interactions between P2X7 and its antagonist, making it a non-ideal target when using pharmacological strategy.
P2Y receptors are also found on both neurons and glial cells. Their role is less clear than that of the P2X receptors, but it has been noted they have several conflicting functions. In some cases, these receptors act as analgesics, as P2Y1 has the ability to inhibit the action of P2X3. In other cases, the receptors contribute to nociception through the modulation of the extracellular concentration of calcitonin gene related peptide (CGRP). These conflicting roles are being researched further so that they may serve as potential targets for the development of a variety of therapeutic drugs.
SGCs also express a specific type of channel, the Kir4.1 channel, which works to maintain the desired low extracellular K+ concentration in order to control hyperexcitability, which is known to cause migraine
s. Additionally, extracellular K+ concentration has been found to be controlled by guanine nucleoside guanosine
(Guo). Guo, which may be involved in neuron-to-SGC communication and interaction in sensory ganglia, is also a potential target that could control the alterations of extracellular K+ concentration associated with chronic pain.
rather than in culture will likely be explored and definitively characterized. Changes in the receptors caused by various mutations and diseases will also be explored in order to determine the impact of these conditions. Additionally, the mechanisms behind neuronal-SGC communication is essentially unidentified, though it is likely that the various receptors both the neurons and SGCs have are used for chemical signaling, perhaps with P2Y. Ca2+ and NO and their impacts must also be observed to gain further understanding of interactions between the two types of cells. Finally, the possibility of an influence of SGCs on synaptic transmission within autonomic ganglia provides another direction for future research.
Glial cell
Glial cells, sometimes called neuroglia or simply glia , are non-neuronal cells that maintain homeostasis, form myelin, and provide support and protection for neurons in the brain, and for neurons in other parts of the nervous system such as in the autonomous nervous system...
that line the exterior surface of neurons 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). Satellite glial cells (SGCs) also surround neuron cell bodies within ganglia. They are of a similar embryological origin to Schwann cells of the PNS, as they are both derived from the neural crest
Neural crest
Neural crest cells are a transient, multipotent, migratory cell population unique to vertebrates that gives rise to a diverse cell lineage including melanocytes, craniofacial cartilage and bone, smooth muscle, peripheral and enteric neurons and glia....
of the embryo during development. SGCs have been found to hold a variety of roles, including control over the microenvironment of sympathetic ganglia. They are thought to have a similar role to astrocytes 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). They supply nutrients to the surrounding neurons and also have some structural function. Satellite cells also act as protective, cushioning cells. Additionally, they express a variety of receptors that allow for a range of interactions with neuroactive chemicals. Many of these receptors and other ion channels have recently been implicated in health issues including chronic pain
Chronic pain
Chronic pain has several different meanings in medicine. Traditionally, the distinction between acute and chronic pain has relied upon an arbitrary interval of time from onset; the two most commonly used markers being 3 months and 6 months since the initiation of pain, though some theorists and...
and herpes simplex
Herpes simplex
Herpes simplex is a viral disease caused by both Herpes simplex virus type 1 and type 2 . Infection with the herpes virus is categorized into one of several distinct disorders based on the site of infection. Oral herpes, the visible symptoms of which are colloquially called cold sores or fever...
. There is much more to be learned about these cells, and research surrounding additional properties and roles of the SGCs is ongoing.
Anatomy
Dorsal root ganglion
In anatomy and neuroscience, a dorsal root ganglion is a nodule on a dorsal root that contains cell bodies of neurons in afferent spinal nerves.-Unique unipolar structure:...
, sympathetic, and parasympathetic ganglia. They compose the thin cellular sheaths that surround the individual neurons in these ganglia.
In an SGC, the cell body is denoted by the region containing the single, relatively large nucleus
Cell nucleus
In cell biology, the nucleus is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these...
. Each side of the cell body extends outward, forming perineuronal processes. The region containing the nucleus has the largest volume of cytoplasm
Cytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...
, making this region of the SGC sheath thicker. The sheath can be even thicker if multiple SGCs are layered on top of one another, each measuring 0.1 μm.
Despite their flattened shape, satellite glial cells contain all common organelles necessary to make cellular products and to maintain the homeostatic environment of the cell. The plasma membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
of SGCs is thin and not very dense, and it is associated with adhesion molecules, receptors for neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
s and other molecules, and ion channel
Ion channel
Ion channels are pore-forming proteins that help establish and control the small voltage gradient across the plasma membrane of cells by allowing the flow of ions down their electrochemical gradient. They are present in the membranes that surround all biological cells...
s, specifically potassium ion channels. Within individual SGCs, there is both rough endoplasmic reticulum
Endoplasmic reticulum
The endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae...
and smooth endoplasmic reticulum, but the latter is much less abundant. Most often the Golgi apparatus
Golgi apparatus
The Golgi apparatus is an organelle found in most eukaryotic cells. It was identified in 1898 by the Italian physician Camillo Golgi, after whom the Golgi apparatus is named....
and the centriole
Centriole
A Centriole is a barrel-shaped cell structure found in most animal eukaryotic cells, though it is absent in higher plants and most fungi. The walls of each centriole are usually composed of nine triplets of microtubules...
s in an SGC are found in a region very close to the cell’s nucleus. On the other hand, mitochondria
Mitochondrion
In cell biology, a mitochondrion is a membrane-enclosed organelle found in most eukaryotic cells. These organelles range from 0.5 to 1.0 micrometers in diameter...
are found throughout the cytoplasm along with the organelles involved in autophagy
Autophagy
In cell biology, autophagy, or autophagocytosis, is a catabolic process involving the degradation of a cell's own components through the lysosomal machinery. It is a tightly regulated process that plays a normal part in cell growth, development, and homeostasis, helping to maintain a balance...
and other forms of catabolic degradation, such as lysosome
Lysosome
thumb|350px|Schematic of typical animal cell, showing subcellular components. [[Organelle]]s: [[nucleoli]] [[cell nucleus|nucleus]] [[ribosomes]] [[vesicle |vesicle]] rough [[endoplasmic reticulum]]...
s, lipofuscin
Lipofuscin
Lipofuscin is the name given to finely granular yellow-brown pigment granules composed of lipid-containing residues of lysosomal digestion. It is considered one of the aging or "wear-and-tear" pigments, found in the liver, kidney, heart muscle, adrenals, nerve cells, and ganglion cells...
granules, and peroxisome
Peroxisome
Peroxisomes are organelles found in virtually all eukaryotic cells. They are involved in the catabolism of very long chain fatty acids, branched chain fatty acids, D-amino acids, polyamines, and biosynthesis of plasmalogens, etherphospholipids critical for the normal function of mammalian brains...
s. Both microtubule
Microtubule
Microtubules are a component of the cytoskeleton. These rope-like polymers of tubulin can grow as long as 25 micrometers and are highly dynamic. The outer diameter of microtubule is about 25 nm. Microtubules are important for maintaining cell structure, providing platforms for intracellular...
s and intermediate filament
Intermediate filament
Intermediate filaments are a family of related proteins that share common structural and sequence features. Intermediate filaments have an average diameter of 10 nanometers, which is between that of 7 nm actin , and that of 25 nm microtubules, although they were initially designated...
s can be seen throughout the cytoplasm, and most often they lie parallel to the SGC sheath. These filaments are found in greater concentrations at the axon hillock
Axon hillock
The axon hillock is a specialized part of the cell body of a neuron that connects to the axon. As a result, the axon hillock is the last site in the soma where membrane potentials propagated from synaptic inputs are summated before being transmitted to the axon. For many years it was believed...
and at the beginning portion of an 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....
in an SGC of the sympathetic ganglia. In some SGCs of the sensory ganglia researchers have seen a single cilium
Cilium
A cilium is an organelle found in eukaryotic cells. Cilia are slender protuberances that project from the much larger cell body....
that extends outward from the cell surface near the nucleus and into the extracellular space of a deep indentation in the plasma membrane. The cilium, however, only has the nine pairs of peripheral microtubules while it lacks the axial pair of microtubules, making its structure very similar to the cilia of neurons, Schwann cells, and astrocytes of the CNS.
In sensory ganglia
Satellite glial cells in sensory ganglia are laminar cells that most often lack any true processes extending from the cell body. In general an envelope of multiple SGCs completely surrounds each sensory neuron. The number of SGCs that make up the sheath increases proportionately with the volume of the neuron which it surrounds. Additionally, the volume of the sheath itself increases proportionately with the volume and surface area of the neuron’s somaSoma
Soma , or Haoma , from Proto-Indo-Iranian *sauma-, was a ritual drink of importance among the early Indo-Iranians, and the subsequent Vedic and greater Persian cultures. It is frequently mentioned in the Rigveda, whose Soma Mandala contains 114 hymns, many praising its energizing qualities...
ta. The distance of extracellular space between the sheath and the neuronal plasma membrane measures 20 nanometre (7.8740157480315E-07 in), allowing the neuron and its SGC sheath to form a single anatomical and functional unit. These individual units are separated by areas of connective tissue. However, there are some sensory neurons that occupy the same space within connective tissue and are therefore grouped together in a “cluster” of two or three neurons. Most often each individual neuron in a cluster is still surrounded by its own SGC sheath, but in some cases it is missing. Some sensory neurons have small projections called microvilli that extend outward from their cell surfaces. Due to their close proximity to the SGC sheath, these microvilli of the neuronal plasma membrane reach into the grooves of the sheath, allowing for possible exchange of materials between the cells.
In sympathetic ganglia
In the sympathetic ganglia, satellite glial cells are one of three main types of cells, the other two being the sympathetic ganglion neurons and small intensely fluorescent (SIF) cellsSmall intensely fluorescent cell
Small intensely fluorescent cells are the interneurons of the sympathetic ganglia of the Sympathetic division of the autonomic nervous system . The neurotransmitter for these cells is dopamine. They are a neural crest derivative and share a common sympathoadrenal precursor cell with sympathetic...
. SIF cells of sympathetic ganglia are separated into groups, each of which is surrounded by an SGC sheath. The SGCs of the sympathetic ganglia come from the neural crest and do not proliferate during embryonic development until the neurons are present and mature, indicating that the neurons signal the division and maturation of the SGCs. The SGCs of sympathetic ganglia follow the same basic structure as the SGCs of sensory ganglia, except that sympathetic ganglia also receive synapse
Synapse
In the nervous system, a synapse is a structure that permits a neuron to pass an electrical or chemical signal to another cell...
s. Therefore, the SGC sheath of sympathetic neurons must extend even further to cover the axon hillock near the somata. Like the regions of the sheath near the glial nucleus, the regions of the sheath at the axon hillocks are thicker than those surrounding the rest of the neuron. This indicates that the SGCs play a role in the synaptic environment, thereby influencing synaptic transmission.
Differences from other glial cells
Many people liken SGCs to the astrocytes of the CNS because they share certain anatomical and physiological properties, such as the presence of neurotransmitter transporters and the expression of glutamine synthetaseGlutamine synthetase
Glutamine synthetase is an enzyme that plays an essential role in the metabolism of nitrogen by catalyzing the condensation of glutamate and ammonia to form glutamine:Glutamate + ATP + NH3 → Glutamine + ADP + phosphate...
. However, there are distinguishing factors that put SGCs in their own distinct category of glial cells. SGCs most often surround individual sensory and parasympathetic neurons with a complete, unbroken sheath while most neurons of sympathetic ganglia lack a completely continuous SGC sheath, allowing for limited direct exchange of materials between the extracellular space of the neuron and the space within the connective tissue
Connective tissue
"Connective tissue" is a fibrous tissue. It is one of the four traditional classes of tissues . Connective Tissue is found throughout the body.In fact the whole framework of the skeleton and the different specialized connective tissues from the crown of the head to the toes determine the form of...
where the SGCs are situated. Furthermore, gap junction
Gap junction
A gap junction or nexus is a specialized intercellular connection between a multitude of animal cell-types. It directly connects the cytoplasm of two cells, which allows various molecules and ions to pass freely between cells....
s exist between SGCs in the sheaths of adjacent neurons as well as between SGCs in the same sheath (reflexive gap junctions). These gap junctions have been identified through the use of electron microscopy
Electron microscope
An electron microscope is a type of microscope that uses a beam of electrons to illuminate the specimen and produce a magnified image. Electron microscopes have a greater resolving power than a light-powered optical microscope, because electrons have wavelengths about 100,000 times shorter than...
and weight tracer markers, such as Lucifer yellow
Lucifer yellow
Lucifer yellow is a fluorescent dye used in cell biology. The key property of Lucifer yellow is that it can readily visualized in both living and fixed cells using a fluorescence microscope. Lucifer yellow was engineered by Walter W. Stewart at NIH and patented in 1978.- Preparations :For common...
or neurobiotin. The degree to which SGCs are coupled to SGCs of another sheath or to SGCs of the same sheath is dependent on the pH
PH
In chemistry, pH is a measure of the acidity or basicity of an aqueous solution. Pure water is said to be neutral, with a pH close to 7.0 at . Solutions with a pH less than 7 are said to be acidic and solutions with a pH greater than 7 are basic or alkaline...
of the cellular environment.
From studies on rats and mice, researchers have found that satellite glial cells express many neurotransmitter receptors, such as muscarinic acetylcholine and erythropoietin
Erythropoietin
Erythropoietin, or its alternatives erythropoetin or erthropoyetin or EPO, is a glycoprotein hormone that controls erythropoiesis, or red blood cell production...
receptors. In order to differentiate between SGCs and other glial cells researchers have used markers to identify which proteins are found in different cells. Although SGCs express glial fibrillary acidic protein
Glial fibrillary acidic protein
Glial fibrillary acidic protein is an intermediate filament protein that was thought to be specific for astrocytes in the central nervous system . Later, it was shown that GFAP is also expressed by other cell types in CNS, including ependymal cells...
(GFAP)and different S-100 protein
S-100 protein
S-100 protein is a family of low molecular weight protein found in vertebrates characterized by two calcium binding sites of the helix-loop-helix conformation. There are at least 21 different types of S100 proteins...
s, the most useful marker available today for SGC identification is glutamine synthetase
Glutamine synthetase
Glutamine synthetase is an enzyme that plays an essential role in the metabolism of nitrogen by catalyzing the condensation of glutamate and ammonia to form glutamine:Glutamate + ATP + NH3 → Glutamine + ADP + phosphate...
(GS). The levels of GS are relatively low at rest, but they greatly increase if the neuron undergoes axonal damage. Furthermore, SGCs also possess mechanisms to release cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
s, adenosine triphosphate
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
(ATP), and other chemical messengers.
Function
Research is currently ongoing in determining the physiological role of satellite glial cells. Current theories suggest that SGCs have a significant role in controlling the microenvironment of the sympathetic ganglia. This is based on the observation that that SGCs almost completely envelop the neuron and can regulate the diffusion of molecules across the cell membrane. It has been previously shown that when fluorescent protein tracers are injected into the cervical ganglion in order to bypass the circulatory systemCirculatory system
The circulatory system is an organ system that passes nutrients , gases, hormones, blood cells, etc...
, they are not found on the neuron surface. This suggests that the SGCs can regulate the extracellular space of individual neurons. Some speculate that SGCs in the autonomic ganglia have a similar role to the blood-brain barrier
Blood-brain barrier
The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...
as a functional barrier to large molecules.
SGCs role as a regulator of neuronal microenvironment is further characterized by its electrical properties which are very similar to that of astrocytes. Astrocytes have a well studied and defined role in controlling the microenvironment within the brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
, therefore researchers are investigating any homologous role of SGCs within the sympathetic ganglia. An established mode of controlling the microenvironment in sensory ganglia is the uptake of substances by specialized transporters which carry neurotransmitters into cells when coupled with Na+ and Cl−. Transporters for glutamate and gamma-Aminobutyric acid
Gamma-aminobutyric acid
γ-Aminobutyric acid is the chief inhibitory neurotransmitter in the mammalian central nervous system. It plays a role in regulating neuronal excitability throughout the nervous system...
(GABA) have been found in SGCs. They appear to be actively engaged in the control of the composition of the extracellular space of the ganglia. The enzyme glutamine synthetase, which catalyzes the conversion of glutamate into glutamine, is found in large amounts in SGCs. Additionally, SGCs contain the glutamate related enzymes glutamate dehydrogenase
Glutamate dehydrogenase
Glutamate dehydrogenase is an enzyme, present in most microbes and the mitochondria of eukaryotes, as are some of the other enzymes required for urea synthesis, that converts glutamate to α-Ketoglutarate, and vice versa. In animals, the produced ammonia is, however, usually bled off to the urea...
and pyruvate carboxylase
Pyruvate carboxylase
Pyruvate carboxylase is an enzyme of the ligase class that catalyzes the irreversible carboxylation of pyruvate to form oxaloacetate .It is an important anaplerotic reaction that creates oxaloacetate from pyruvate...
, and thus can supply the neurons not only with glutamine, but also with malate
Malate
Malate is the ionized form of malic acid. It is an important chemical compound in biochemistry. In the C4 carbon fixation process, malate is a source of CO2 in the Calvin cycle....
and lactate
Lactate
Lactate may refer to:*The act of lactation*The conjugate base of lactic acid...
.
Molecular properties
Unlike their adjacent neurons, SGCs do not have synapses but are equipped with receptors for a variety of neuroactive substances that are analogous to those found in neurons. Axon terminals as well as other parts of the neuron carry receptors to substances such as acetylcholineAcetylcholine
The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...
(ACh), GABA, glutamate, ATP, noradrenaline, substance P
Substance P
In the field of neuroscience, substance P is a neuropeptide: an undecapeptide that functions as a neurotransmitter and as a neuromodulator. It belongs to the tachykinin neuropeptide family. Substance P and its closely related neuropeptide neurokinin A are produced from a polyprotein precursor...
, and capsaicin
Capsaicin
Capsaicin 2CHCH=CH4CONHCH2C6H3-4--3- ) is the active component of chili peppers, which are plants belonging to the genus Capsicum. It is an irritant for mammals, including humans, and produces a sensation of burning in any tissue with which it comes into contact...
that directly affect the physiology of these cells. Current research is revealing that SGCs are also able to respond to some of the same chemical stimuli as neurons. The research is ongoing and SGCs role in injury repair mechanisms is not yet fully understood.
Molecular characteristics of SGCs
| Molecule | Type of Ganglia | Method of Detection | Comments |
|---|---|---|---|
| Glutamine synthetase | Mouse TG Trigeminal ganglion The trigeminal ganglion is a sensory ganglion of the trigeminal nerve that occupies a cavity in the dura mater, covering the trigeminal impression near the apex of the petrous part of the temporal bone.-Relations:It is somewhat crescentic in shape, with its convexity... |
IHC Immunohistochemistry Immunohistochemistry or IHC refers to the process of detecting antigens in cells of a tissue section by exploiting the principle of antibodies binding specifically to antigens in biological tissues. IHC takes its name from the roots "immuno," in reference to antibodies used in the procedure, and... |
Catalyzes the condensation of glutamate and ammonia to form glutamine |
| GFAP | Rat DRG Dorsal root ganglion In anatomy and neuroscience, a dorsal root ganglion is a nodule on a dorsal root that contains cell bodies of neurons in afferent spinal nerves.-Unique unipolar structure:... , TG |
IHC | Upregulated by nerve damage |
| S100 S-100 protein S-100 protein is a family of low molecular weight protein found in vertebrates characterized by two calcium binding sites of the helix-loop-helix conformation. There are at least 21 different types of S100 proteins... |
Rat DRG | IHC | Upregulated by nerve damage |
| Endothelin ETB receptor Endothelin receptor type B Endothelin receptor type B, also known as ETB is a protein that in humans is encoded by the EDNRB gene.- Function :Endothelin receptor type B is a G protein-coupled receptor which activates a phosphatidylinositol-calcium second messenger system. Its ligand, endothelin, consists of a family of three... |
Rat, rabbit DRG | IHC, autoradiography Autoradiograph An autoradiograph is an image on an x-ray film or nuclear emulsion produced by the pattern of decay emissions from a distribution of a radioactive substance... |
Blockers of ETs are shown to alleviate pain in animal models |
| Bradykinin B2 receptor Bradykinin receptor B2 Bradykinin receptor B2 is a G-protein coupled receptor for bradykinin, encoded by the BDKRB2 gene in humans.-Mechanism:The B2 receptor is a G protein-coupled receptor, probably coupled to Gq and Gi. Gq stimulates phospholipase C to increase intracellular free calcium and Gi inhibits adenylate cyclase... |
Rat DRG | Electrophysiology Electrophysiology Electrophysiology is the study of the electrical properties of biological cells and tissues. It involves measurements of voltage change or electric current on a wide variety of scales from single ion channel proteins to whole organs like the heart... |
Involved in the inflammatory process |
| P2Y receptor P2Y receptor P2Y receptors are a family of purinergic receptors, G protein-coupled receptors stimulated by nucleotides such as ATP, ADP, UTP, UDP and UDP-glucose... |
Mouse TG | Ca2+ imaging Calcium imaging Calcium imaging is a scientific technique usually carried out in research which is designed to show the calcium status of a tissue or medium.... , IHC |
Contributes to nociception |
| ACh muscarinic receptor Muscarinic acetylcholine receptor Muscarinic receptors, or mAChRs, are acetylcholine receptors that form G protein-coupled in the plasma membranes of certain neurons and other cells... |
Rat DRG | IHC, mRNA Messenger RNA Messenger RNA is a molecule of RNA encoding a chemical "blueprint" for a protein product. mRNA is transcribed from a DNA template, and carries coding information to the sites of protein synthesis: the ribosomes. Here, the nucleic acid polymer is translated into a polymer of amino acids: a protein... (ISH In situ hybridization In situ hybridization is a type of hybridization that uses a labeled complementary DNA or RNA strand to localize a specific DNA or RNA sequence in a portion or section of tissue , or, if the tissue is small enough , in the entire tissue... ) |
Role not well defined in sensory ganglia |
| NGF trkA receptor Nerve growth factor receptor Nerve growth factor receptors are a group of growth factor receptors which specifically bind to neurotrophins.There are two classes of receptors, p75 and the "Trk" family of Tyrosine kinases receptors.... |
Rat DRG | Immuno-EM Immunostaining Immunostaining is a general term in biochemistry that applies to any use of an antibody-based method to detect a specific protein in a sample. The term immunostaining was originally used to refer to the immunohistochemical staining of tissue sections, as first described by Albert Coons in 1941... |
May play a role in response to neuronal injury |
| TGFα TGF alpha Transforming growth factor alpha is upregulated in some human cancers. It is produced in macrophages, brain cells, and keratinocytes, and induces epithelial development. It is closely related to EGF, and can also bind to the EGF receptor with similar effects... |
Rat DRG | mRNA (ISH), IHC | Stimulates neural proliferation after injury |
| Erythropoietin receptor Erythropoietin receptor The erythropoietin receptor is a protein that in humans is encoded by the EPOR gene. EpoR is a 59 kDa peptide and is a member of the cytokine receptor family. EpoR pre-exists as dimers... |
Rat DRG | IHC | |
| TNF-α | Mouse DRG, TG | IHC | Inflammatory mediator increased by nerve crush, herpes simplex activation |
| IL-6 Interleukin 6 Interleukin-6 is a protein that in humans is encoded by the IL6 gene.IL-6 is an interleukin that acts as both a pro-inflammatory and anti-inflammatory cytokine. It is secreted by T cells and macrophages to stimulate immune response, e.g. during infection and after trauma, especially burns or other... |
Mouse TG | IHC | Cytokine released during inflammation, increased by UV irradiation |
| ERK Extracellular signal-regulated kinases In molecular biology, extracellular-signal-regulated kinases or classical MAP kinases are widely expressed protein kinase intracellular signalling molecules that are involved in functions including the regulation of meiosis, mitosis, and postmitotic functions in differentiated cells... |
Rat DRG | IHC | Involved in functions including the regulation of meiosis Meiosis Meiosis is a special type of cell division necessary for sexual reproduction. The cells produced by meiosis are gametes or spores. The animals' gametes are called sperm and egg cells.... , and mitosis Mitosis Mitosis is the process by which a eukaryotic cell separates the chromosomes in its cell nucleus into two identical sets, in two separate nuclei. It is generally followed immediately by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two cells containing roughly... |
| JAK2 Janus kinase 2 Janus kinase 2 is a human protein that has been implicated in signaling by members of the type II cytokine receptor family , the GM-CSF receptor family , the gp130 receptor family , and the single chain receptors... |
Rat DRG | IHC | Signaling protein apart of the type II cytokine receptor Type II cytokine receptor Type II cytokine receptors are transmembrane proteins that are expressed on the surface of certain cells, which bind and respond to a select group of cytokines... family |
| Somatostatin sst1 receptor Somatostatin receptor 1 Somatostatin receptor type 1 is a protein that in humans is encoded by the SSTR1 gene.... |
Rat DRG | IHC | Somatostatin inhibits the release of many hormones and other secretory proteins |
| GABA transporter | Rat DRG | Autoradiography | |
| Glutamate transporter | Rat DRG | mRNA (ISH), IHC, Autoradiography | Terminates the excitatory neurotransmitter signal by removal (uptake) of glutamate |
| Guanylate cyclase Guanylate cyclase -Reaction:Guanylate cyclase catalyzes the reaction of guanosine triphosphate to 3',5'-cyclic guanosine monophosphate and pyrophosphate:-Types:... |
Rat DRG, TG | IHC for cGMP Cyclic guanosine monophosphate Cyclic guanosine monophosphate is a cyclic nucleotide derived from guanosine triphosphate . cGMP acts as a second messenger much like cyclic AMP... |
Second messenger that internalizes the message carried by intercellular messengers such as peptide hormones and NO |
| PGD synthase Prostaglandin D2 synthase Prostaglandin-H2 D-isomerase is an enzyme that in humans is encoded by the PTGDS gene.-Further reading:... |
Chick DRG | IHC | Known to function as a neuromodulator as well as a trophic factor in the central nervous system |
Chronic pain
Glial cells, including SGCs, have long been recognized for their roles in response to neuronal damage and injury. SCGs have specifically been implicated in a new role involving the creation and persistence of chronic pain, which may involve hyperalgesiaHyperalgesia
Hyperalgesia is an increased sensitivity to pain, which may be caused by damage to nociceptors or peripheral nerves. Temporary increased sensitivity to pain also occurs as part of sickness behavior, the evolved response to infection.-Types:...
and other forms of spontaneous pain.
Secretion of bioactive molecules
SGCs have the ability to release cytokines and other bioactive molecules that transmit pain neuronally. Neurotrophins and tumor necrosis factor α (TNFα) are other cellular factors that work to sensitize neurons to pain. SGCs are present in the PNS in fewer numbers than other more well-known types of glial cells, like astrocytes, but have been determined to have an impact on nociceptionNociception
Nociception is defined as "the neural processes of encoding and processing noxious stimuli." It is the afferent activity produced in the peripheral and central nervous system by stimuli that have the potential to damage tissue...
because of some of their physiological and pharmacological properties. In fact, just like astrocytes, SGCs have the ability to sense and regulate neighboring neuronal activity. First, after a period of nerve cell injury, SGCs are known to up-regulate GFAP and to undergo cell division. They have the ability to release chemoattractants
Chemotaxis
Chemotaxis is the phenomenon in which somatic cells, bacteria, and other single-cell or multicellular organisms direct their movements according to certain chemicals in their environment. This is important for bacteria to find food by swimming towards the highest concentration of food molecules,...
, which are analogous to those released by Schwann cells and contribute to the recruitment and proliferation of macrophages. Additionally, several research groups have found that SGC coupling increases after nerve damage, which has an effect on the perception of pain, likely for several reasons. Normally, the gap junctions between SGCs are used in order to redistribute potassium ions between adjacent cells. However, in coupling of SGCs, the number of gap junctions greatly increases. This may possibly be to deal with larger amounts of ATP and glutamate, which eventually leads to increased recycling of the glutamate. The increased levels of glutamate lead to over excitation and an increase in nociception.
Expression of receptors and ion channels
Various neuronal receptors present on SGCs have been named as participants in ATP-evoked pain signals, particularly the homomultimer P2X3 and the heteromultimer P2X2/3 purinoceptors. In general, the P2X family of receptors responds to neuronally released ATP. Each of the P2X subtypes are found in sensory neurons with the exception of the P2X7 receptor, which is selectively expressed by glial cells, including SGCs. The receptor has been implicated in the release of interleukin IL-1βIL1B
Interleukin-1 beta also known as catabolin, is a cytokine protein that in humans is encoded by the IL1B gene. IL-1β precursor is cleaved by caspase 1 . Cytosolic thiol protease cleaves the product to form mature IL-1β.- Function :Interleukin 1 was discovered by Gery in 1972...
from macrophages or microglia and astrocytes. The receptor likely has a part in the cascade of events that end with inflammation and neuropathic pain. It has been discovered that this receptor has an antagonist in the form of A-317491, which, when present, has the ability to reduce both the evoked and unprompted firing of various classes of spinal neurons, as well as to inhibit release of IL-1β. However, the outside influences of receptors P2X3 and P2Y1
P2RY1
P2Y purinoceptor 1 is a protein that in humans is encoded by the P2RY1 gene.-Further reading:...
are believed to complicate the interactions between P2X7 and its antagonist, making it a non-ideal target when using pharmacological strategy.
P2Y receptors are also found on both neurons and glial cells. Their role is less clear than that of the P2X receptors, but it has been noted they have several conflicting functions. In some cases, these receptors act as analgesics, as P2Y1 has the ability to inhibit the action of P2X3. In other cases, the receptors contribute to nociception through the modulation of the extracellular concentration of calcitonin gene related peptide (CGRP). These conflicting roles are being researched further so that they may serve as potential targets for the development of a variety of therapeutic drugs.
SGCs also express a specific type of channel, the Kir4.1 channel, which works to maintain the desired low extracellular K+ concentration in order to control hyperexcitability, which is known to cause migraine
Migraine
Migraine is a chronic neurological disorder characterized by moderate to severe headaches, and nausea...
s. Additionally, extracellular K+ concentration has been found to be controlled by guanine nucleoside guanosine
Guanosine
Guanosine is a purine nucleoside comprising guanine attached to a ribose ring via a β-N9-glycosidic bond. Guanosine can be phosphorylated to become guanosine monophosphate , cyclic guanosine monophosphate , guanosine diphosphate , and guanosine triphosphate...
(Guo). Guo, which may be involved in neuron-to-SGC communication and interaction in sensory ganglia, is also a potential target that could control the alterations of extracellular K+ concentration associated with chronic pain.
Herpes simplex
Sensory ganglia have been associated with infections from viruses like herpes simplex, which can exist in a dormant state within the ganglia for decades after the primary infection. When the virus becomes reactivated, blisters on the skin and mucous membranes appear. During the latent stage of the virus, the viruses are rarely located in the SGCs within the sensory ganglia, but the SGCs may still play an important role within the disease. It has been proposed that SGCs act to create walls to prevent the spread of the virus from infected to uninfected neurons. If this wall of protection was to break down, then the infection could become more widespread. This property may be explained by looking at the location and arrangement of the SGCs, as they are centered on the neurons, allowing them to protect the neurons. It has also been proposed that SGCs may have a job in ridding the ganglia of the virus and in protecting and repairing the nervous system after the virus has left the dormant stage.Research directions
The majority of the information available on the subject of SGCs comes from research which was focused on the sensory neurons that the SGCs surround rather than the SGCs themselves. In the future, researchers plan to give more time and attention to the SGCs, which have many supportive and protective functions essential for life. Neurotransmitter and hormone receptors on SGCs in situIn situ
In situ is a Latin phrase which translated literally as 'In position'. It is used in many different contexts.-Aerospace:In the aerospace industry, equipment on board aircraft must be tested in situ, or in place, to confirm everything functions properly as a system. Individually, each piece may...
rather than in culture will likely be explored and definitively characterized. Changes in the receptors caused by various mutations and diseases will also be explored in order to determine the impact of these conditions. Additionally, the mechanisms behind neuronal-SGC communication is essentially unidentified, though it is likely that the various receptors both the neurons and SGCs have are used for chemical signaling, perhaps with P2Y. Ca2+ and NO and their impacts must also be observed to gain further understanding of interactions between the two types of cells. Finally, the possibility of an influence of SGCs on synaptic transmission within autonomic ganglia provides another direction for future research.