Trk receptor
Encyclopedia
Trk receptors are a family of tyrosine kinases
that regulates synaptic
strength and plasticity
in the mammalian nervous system
. Trk receptors affect neuron
al survival and differentiation
through several signal cascades. However, the activation of these receptors also has significant effects on functional properties of neurons.
The common ligands of trk receptors are neurotrophin
s, a family of growth factor
s critical to the functioning of the nervous system. The binding
of these molecules is highly specific. Each type of neurotrophin has different binding affinity toward its corresponding trk receptor. The activation of Trk receptors by neurotrophin binding may lead to activation of signal cascades resulting in promoting survival and other functional regulation of cells.
-receptor
-kinase
(and not tyrosine kinase nor tropomyosin-related kinase, as has been commonly mistaken).
The family of Trk receptors is named for the oncogene
trk, whose identifical led to the discovery of its first member, TrkA
. trk, initially identified in a colon carcinoma, is frequently (25%) activated in thyroid papillary carcinoma
s. The oncogene was generated by a mutation
in chromosome 1
that resulted in the fusion
of the first seven exon
s of tropomyosin to the transmembrane and cytoplasm
ic domains of the then-unknown TrkA receptor. Normal Trk receptors do not contain amino acid
or DNA sequences
related to tropomyosin.
Neurotrophin ligands of Trk receptors are processed ligands, meaning that they are synthesized in immature forms and then transformed by protease
cleavage. Immature neurotrophins are specific only to one common p75NTR receptor. However, protease cleavage generates neurotrophins that have higher affinity to their corresponding Trk receptors. These processed neurotrophins can still bind to p75NTR, but at a much lower affinity.
has the highest affinity to the binding nerve growth factor
(NGF). NGF is important in both local and nuclear actions, regulating growth cones, motility
, and expression of genes
encoding the biosynthesis enzymes for neurotransmitters. Nociceptive sensory neurons express mostly trkA and not trkB or trkC.
has the highest affinity to the binding of brain-derived neurotrophic factor
(BDNF) and NT-4
. BDNF is a growth factor that has important roles in the survival and function of neurons in the central nervous system
. The binding of BDNF to TrkB receptor causes many intercellular cascades
be activated, which regulate neuronal development
and plasticity
, long-term potentiation
, and apoptosis
.
Although both BDNF and NT-4 have high specificity to TrkB, they are not interchangeable. In a mouse model study where BDNF expression was replaced by NT-4, the mouse with NT4 expression appeared to be smaller and exhibited decreased fertility.
Recently, studies have also indicated that TrkB receptor is associated with Alzheimer's disease
.
is ordinarily activated by binding with NT-3 and has little activation by other ligands. (TrkA and TrkB also bind NT-3, but to a lesser extent.) TrkC is mostly expressed by proprioceptive sensory neurons. The axon
s of these proprioceptive sensory neurons are much thicker than those of nocireceptive sensory neurons, which express trkA.
s on TrkA. However, the binding of ligands in p75NTR is not required to promote high-affinity binding. Therefore, the data suggest that the presence of p75NTR affects the conformation of TrkA, preferentially the state with high-affinity binding site for NGF. Surprisingly, although the presence of p75NTR is essential to promote high-affinity binding, the NT3 binding to the receptor is not required.
Apart from affecting the affinity and specificity for Trk receptor, P75 neurotropins receptor (P75NTR) can also reduce ligand-induced receptor ubiquitination, delays receptor internalization, and degradation. In an experiment by Makkerh in 2005, both TrkA and TrkB receptors were tested using similar method. The only difference is that NGF was used to activate the TrkA receptor whereas BDNF was used for TrkB receptor.
in 5 min. The biotinylated protein complex
es were lysed to show both tyrosine-phosphorylated molecules in the surface and those that been internalized.
and in vitro
, have shown that neurotrophins have proliferation and differentiation effects on CNS neuro-epithelial precursors, neural crest cells, or precursors of the enteric nervous system
. TrkA that expresses NGF not only increase the survival of both C and A delta classes of nocireceptor neurons, but also affect the functional properties of these neurons.4 As mentioned before, BDNF improves the survival and function of neurons in CNS, particularly cholinergic neurons of the basal forebrain
, as well as neurons in the hippocampus and cortex.
BDNF belongs to the neurotrophin family of growth factors and affects the survival and function of neurons in the central nervous system, particularly in brain regions susceptible to degeneration in AD. BDNF improves survival of cholinergic neurons of the basal forebrain, as well as neurons in the hippocampus and cortex.
TrkC that expresses NT3 has been shown to promote proliferation and survival of cultured neural crest
cells, oligodendrocyte precursors, and differentiation of hippocampal neuron precursors.
outgrowth. NGF/TrkA signaling regulates the advance of sympathetic
neuron growth cones; even when neurons received adequate trophic (sustaining and nourishing) support, one experiment showed they did not grow into relating compartments without NGF. NGF increases the innervation of tissues that receive sympathetic or sensory innervation and induces aberrant innervation in tissues that are normally not innervated.
NGF/TrkA signaling upregulates BDNF, which is transported to both peripheral and central terminals of nocireceptive sensory neurons. In the periphery, TrkB/BDNF binding and TrkB/NT-4
binding acutely sensitizing nocireceptive pathway that require the presence of mast cell
s.
s formed between afferent neurons and motor neuron
s. Increased NT-3/trkC binding results in larger monosynaptic
excitatory postsynaptic potential
s (EPSPs) and reduced polysynaptic
components. On the other hand, increased NT-3 binding to trkB to BDNF has the opposite effect, reducing the size of monosynaptic excitatory postsynaptic potentials (EPSPs) and increasing polysynaptic signaling.
(LGN) and terminate in separate layers of striate cortex
. However, axons from each LGN can only be driven by one side of the eye, but not both together. tThese axons that terminate in layer IV of the striate cortex result in ocular dominance
columns. A study shows that The density of innervating axons in layer IV from LGN can be increased by exogenous BDNF and reduced by a scavenger of endogenous BDNF. Therefore, it raises the possibility that both of these agents are involved in some sorting mechanism that is not well comprehended yet. Previous studies with cat model has shown that monocular deprivation
occurs when input to one of the mammalian eyes is absent during the critical period (critical window). However, A study demonstrated that the infusion of NT-4 (a ligand of trkB) into the visual cortex during the critical period has been shown to prevent many consequences of monocular deprivation
. Surprisingly, even after losing responses during the critical period, the infusion of NT-4 has been shown to be able to restore them.
, the axons of the CA3 pyramidal cell
s project into CA1 cells through the Schaffer collaterals. The long-term potentiation
(LTP) may induce in either of these pathways, but it is specific only to the one that is stimulated with tetanus
. The stimulated axon does not impact spill over to the other pathway. TrkB receptors are expressed in most of these hippocampal neurons, including dentate
granule cell
s, CA3 and CA1 pyramidal cells, and inhibitory interneurons. Interestingly, LTP can be greatly reduced by BDNF mutants. In a similar study on a mouse mutant with reduced expression of trkB receptors, LTP of CA1 cells reduced significantly. TrkB loss has also been linked to interfere with the memory acquisition and consolidation in many learning paradigm.
in response to ligand, as do other tyrosine kinase receptors. These dimers phosphorylate each other and enhance catalytic activity
of the kinase. Trk receptors affect neuronal growth and differentiation through the activation of different signaling cascades. The three known pathways are PLC, Ras/MAPK (mitogen-activated protein kinase)
and the PI3K (phosphatidylinositol 3-kinase) pathways. These pathways involve the interception of nuclear and mitochondrial cell-death programs. These signaling cascades eventually led to the activation of a transcription factor
, CREB
(cAMP response element-binding), which in turn activate the target genes.
will lead to the phosphorylation of phospholipase C
(PLC) by trk receptor. This phosphorylation of PLC induces an enzyme to catalyze the breakdown of lipids to diacyglycerol and inositol(1,4, 5). Diacyglycerol may indirectly activate PI3 kinase or several protein kinase C
(PKC) isoforms, whereas inositol(1,4, 5) promotes release of calcium from intracellular stores.
is important for the neurotrophin-induced differentiation of neuronal and neuroblastoma
cells. Phosphorylation of tyrosine residues in the Trk receptors led to the activation of Ras molecules, H-Ras and K-Ras. H-ras is found in lipid raft
s, embedded within the plasma membrane
, while K-Ras is predominantly found in disordered region of the membrane. RAP, a vesicle bounded molecule that also takes part in the cascading, is localized in the intracellular region.
The activation of these molecules result in two alternative MAP kinase
pathways. Erk 1,2 can be stimulated through the activation cascades of K-Ras, Raf1, and MEK 1,2, whereas ERK5 is stimulated through the activation cascades of B-Raf, MEK5, and Erk 5. However, whether PKC (protein kinase C) could activate MEK5 is not yet known.
signaling is critical for both mediation of neurotrophin-induced survival and regulation of vesicular trafficking. The trk receptor stimulates P13 heterodimers, which causes the activation of kinases PDK-1 and Akt
. Akt in turn stimulates FRK (Forkhead family transcription factor), BAD, and GSK-3
.
Receptor tyrosine kinase
Receptor tyrosine kinases s are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinase proteins....
that regulates synaptic
Chemical synapse
Chemical synapses are specialized junctions through which neurons signal to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the central nervous system. They are crucial to the biological computations that underlie...
strength and plasticity
Synaptic plasticity
In neuroscience, synaptic plasticity is the ability of the connection, or synapse, between two neurons to change in strength in response to either use or disuse of transmission over synaptic pathways. Plastic change also results from the alteration of the number of receptors located on a synapse...
in the mammalian nervous system
Nervous system
The nervous system is an organ system containing a network of specialized cells called neurons that coordinate the actions of an animal and transmit signals between different parts of its body. In most animals the nervous system consists of two parts, central and peripheral. The central nervous...
. Trk receptors affect 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...
al survival and differentiation
Cellular differentiation
In developmental biology, cellular differentiation is the process by which a less specialized cell becomes a more specialized cell type. Differentiation occurs numerous times during the development of a multicellular organism as the organism changes from a simple zygote to a complex system of...
through several signal cascades. However, the activation of these receptors also has significant effects on functional properties of neurons.
The common ligands of trk receptors are neurotrophin
Neurotrophin
Neurotrophins are a family of proteins that induce the survival, development, and function of neurons.They belong to a class of growth factors, secreted proteins that are capable of signaling particular cells to survive, differentiate, or grow. Growth factors such as neurotrophins that promote the...
s, a family of growth factor
Growth factor
A growth factor is a naturally occurring substance capable of stimulating cellular growth, proliferation and cellular differentiation. Usually it is a protein or a steroid hormone. Growth factors are important for regulating a variety of cellular processes....
s critical to the functioning of the nervous system. The binding
Binding (molecular)
Molecular binding is an attractive interaction between two molecules which results in a stable association in which the molecules are in close proximity to each other...
of these molecules is highly specific. Each type of neurotrophin has different binding affinity toward its corresponding trk receptor. The activation of Trk receptors by neurotrophin binding may lead to activation of signal cascades resulting in promoting survival and other functional regulation of cells.
Origin of the name trk
The abbreviation trk (often pronounced 'track') stands for tropomyosinTropomyosin
Tropomyosin is an actin-binding protein that regulates actin mechanics. It is important, among other things, for muscle contraction. Tropomyosin, along with the troponin complex, associate with actin in muscle fibers and regulate muscle contraction by regulating the binding of myosin...
-receptor
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
-kinase
Kinase
In chemistry and biochemistry, a kinase is a type of enzyme that transfers phosphate groups from high-energy donor molecules, such as ATP, to specific substrates, a process referred to as phosphorylation. Kinases are part of the larger family of phosphotransferases...
(and not tyrosine kinase nor tropomyosin-related kinase, as has been commonly mistaken).
The family of Trk receptors is named for the oncogene
Oncogene
An oncogene is a gene that has the potential to cause cancer. In tumor cells, they are often mutated or expressed at high levels.An oncogene is a gene found in the chromosomes of tumor cells whose activation is associated with the initial and continuing conversion of normal cells into cancer...
trk, whose identifical led to the discovery of its first member, TrkA
TrkA
High affinity nerve growth factor receptor also known as neurotrophic tyrosine kinase receptor type 1 or TRK1-transforming tyrosine kinase protein or Trk-A is a protein that in humans is encoded by the NTRK1 gene....
. trk, initially identified in a colon carcinoma, is frequently (25%) activated in thyroid papillary carcinoma
Thyroid cancer
Thyroid neoplasm is a neoplasm or tumor of the thyroid. It can be a benign tumor such as thyroid adenoma, or it can be a malignant neoplasm , such as papillary, follicular, medullary or anaplastic thyroid cancer. Most patients are 25 to 65 years of age when first diagnosed; women are more affected...
s. The oncogene was generated by a mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
in chromosome 1
Chromosome 1 (human)
Chromosome 1 is the designation for the largest human chromosome. Humans have two copies of chromosome 1, as they do with all of the autosomes, which are the non-sex chromosomes. Chromosome 1 spans about 247 million nucleotide base pairs, which are the basic units of information for DNA...
that resulted in the fusion
Fusion gene
A fusion gene is a hybrid gene formed from two previously separate genes. It can occur as the result of a translocation, interstitial deletion, or chromosomal inversion...
of the first seven exon
Exon
An exon is a nucleic acid sequence that is represented in the mature form of an RNA molecule either after portions of a precursor RNA have been removed by cis-splicing or when two or more precursor RNA molecules have been ligated by trans-splicing. The mature RNA molecule can be a messenger RNA...
s of tropomyosin to the transmembrane and 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...
ic domains of the then-unknown TrkA receptor. Normal Trk receptors do not contain amino acid
Primary structure
The primary structure of peptides and proteins refers to the linear sequence of its amino acid structural units. The term "primary structure" was first coined by Linderstrøm-Lang in 1951...
or DNA sequences
DNA sequencing
DNA sequencing includes several methods and technologies that are used for determining the order of the nucleotide bases—adenine, guanine, cytosine, and thymine—in a molecule of DNA....
related to tropomyosin.
Trk receptor types and corresponding ligands
The three most common types of trk receptors are trkA, trkB, and trkC. Each of these receptor types has different binding affinity to certain types of neurotrophins. The differences in the signaling initiated by these distinct types of receptors are important for generating diverse of biological responses.Neurotrophin ligands of Trk receptors are processed ligands, meaning that they are synthesized in immature forms and then transformed by protease
Protease
A protease is any enzyme that conducts proteolysis, that is, begins protein catabolism by hydrolysis of the peptide bonds that link amino acids together in the polypeptide chain forming the protein....
cleavage. Immature neurotrophins are specific only to one common p75NTR receptor. However, protease cleavage generates neurotrophins that have higher affinity to their corresponding Trk receptors. These processed neurotrophins can still bind to p75NTR, but at a much lower affinity.
TrkA
TrkATrkA
High affinity nerve growth factor receptor also known as neurotrophic tyrosine kinase receptor type 1 or TRK1-transforming tyrosine kinase protein or Trk-A is a protein that in humans is encoded by the NTRK1 gene....
has the highest affinity to the binding nerve growth factor
Nerve growth factor
Nerve growth factor is a small secreted protein that is important for the growth, maintenance, and survival of certain target neurons . It also functions as a signaling molecule. It is perhaps the prototypical growth factor, in that it is one of the first to be described...
(NGF). NGF is important in both local and nuclear actions, regulating growth cones, motility
Motility
Motility is a biological term which refers to the ability to move spontaneously and actively, consuming energy in the process. Most animals are motile but the term applies to single-celled and simple multicellular organisms, as well as to some mechanisms of fluid flow in multicellular organs, in...
, and expression of genes
Gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...
encoding the biosynthesis enzymes for neurotransmitters. Nociceptive sensory neurons express mostly trkA and not trkB or trkC.
TrkB
TrkBTrkB
TrkB receptor also known as TrkB tyrosine kinase or BDNF/NT-3 growth factors receptor or neurotrophic tyrosine kinase, receptor, type 2 is a protein that in humans is encoded by the NTRK2 gene.-Function:...
has the highest affinity to the binding of brain-derived neurotrophic factor
Brain-derived neurotrophic factor
Brain-derived neurotrophic factor, also known as BDNF, is a protein that, in humans, is encoded by the BDNF gene. BDNF is a member of the "neurotrophin" family of growth factors, which are related to the canonical "Nerve Growth Factor", NGF...
(BDNF) and NT-4
NT-4
Neurotrophin-4 , also known as neurotrophin-5 , is a protein that in humans is encoded by the NTF4 gene.NT-4 is a neurotrophic factor that signals predominantly through the TrkB receptor tyrosine kinase....
. BDNF is a growth factor that has important roles in the survival and function of neurons 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...
. The binding of BDNF to TrkB receptor causes many intercellular cascades
Biochemical cascade
A biochemical cascade is a series of chemical reactions in which the products of one reaction are consumed in the next reaction. There are several important biochemical cascade reactions in biochemistry, including the enzymatic cascades, such as the coagulation cascade and the complement system,...
be activated, which regulate neuronal development
Neural development
Neural development comprises the processes that generate, shape, and reshape the nervous system, from the earliest stages of embryogenesis to the final years of life. The study of neural development aims to describe the cellular basis of brain development and to address the underlying mechanisms...
and plasticity
Neuroplasticity
Neuroplasticity is a non-specific neuroscience term referring to the ability of the brain and nervous system in all species to change structurally and functionally as a result of input from the environment. Plasticity occurs on a variety of levels, ranging from cellular changes involved in...
, long-term potentiation
Long-term potentiation
In neuroscience, long-term potentiation is a long-lasting enhancement in signal transmission between two neurons that results from stimulating them synchronously. It is one of several phenomena underlying synaptic plasticity, the ability of chemical synapses to change their strength...
, and apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
.
Although both BDNF and NT-4 have high specificity to TrkB, they are not interchangeable. In a mouse model study where BDNF expression was replaced by NT-4, the mouse with NT4 expression appeared to be smaller and exhibited decreased fertility.
Recently, studies have also indicated that TrkB receptor is associated with Alzheimer's disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
.
TrkC
TrkCTrkC
NT-3 growth factor receptor also known as neurotrophic tyrosine kinase receptor type 3 or TrkC tyrosine kinase or Trk-C receptor is a protein that in humans is encoded by the NTRK3 gene....
is ordinarily activated by binding with NT-3 and has little activation by other ligands. (TrkA and TrkB also bind NT-3, but to a lesser extent.) TrkC is mostly expressed by proprioceptive sensory neurons. 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....
s of these proprioceptive sensory neurons are much thicker than those of nocireceptive sensory neurons, which express trkA.
P75NTR increases binding affinity and specificity for Trk receptor
p75NTR (p75 neurotrophin receptor) affects the binding affinity and specificity of Trk receptor activation by neurotrophins. The presence of p75NTR is especially important in increasing the binding affinity of NGF to TrkA. Although the dissociation constants of p75NTR and TrkA are remarkably similar, their kinetics are quite different. Reduction and mutation of cytoplasmic and transmembrane domains of either TrkA or P75NTR prevent the formation of high-affinity binding siteBinding site
In biochemistry, a binding site is a region on a protein, DNA, or RNA to which specific other molecules and ions—in this context collectively called ligands—form a chemical bond...
s on TrkA. However, the binding of ligands in p75NTR is not required to promote high-affinity binding. Therefore, the data suggest that the presence of p75NTR affects the conformation of TrkA, preferentially the state with high-affinity binding site for NGF. Surprisingly, although the presence of p75NTR is essential to promote high-affinity binding, the NT3 binding to the receptor is not required.
Apart from affecting the affinity and specificity for Trk receptor, P75 neurotropins receptor (P75NTR) can also reduce ligand-induced receptor ubiquitination, delays receptor internalization, and degradation. In an experiment by Makkerh in 2005, both TrkA and TrkB receptors were tested using similar method. The only difference is that NGF was used to activate the TrkA receptor whereas BDNF was used for TrkB receptor.
TrkA and TrkB receptors activity are ligand-dependent
To test if TrkA and TrkB receptors activity are ligand-dependent, the receptors are treated with NGF and BDNF correspondingly. In vivo, the activity of these receptors is regulated by ubiquitination, the process in which protein undergoes modification by attachment of ubiquitin monomers. These molecules usually have main function of labeling proteins for proteasomal degradation. After being activated, Trk receptors may undergo endocytosis and will be either recycled or degraded. Two types of cells were used to test the protocol, PC12 cells and E16 mouse cortices. An E16 mouse cortex was used in conjunction with BDNF, since it expresses abundant TrkB and lesser p75NTR. On the other hands, PC12 cells were treated with NGF, since it expresses more TrkA and p75NTR but not TrkB and TrkC. The treated receptors were then immunoprecipitated and immunoblotted to be analyzed. The result shows that TrkB phosphotyrosine (activated TrkB) content increased rapidly with the presence of BDNF compared with control (absence of BDNF) whereas TrkA phosphotyrosine content increased modestly when treated with NGF.p75NTR reduces Trk ubiquitination
To test if p75NTR reduces Trk ubiquitination, HEK293 (human embryonic kidney 293 cells) were co-tranfected with plasmids encoding TrkA and Myc-tagged ubiquitin with the presence and absence of plasmid encoding p75NTR. When treated with their corresponding neurotrophins, lower levels of ubiquitinated TrkA and TrkB are present in presence of p75NTR. Vice versa, in the absence of p75NTR, ubiquitination content increases decreases significantly.p75NTR delays Trk receptor internalization
To test the hypothesis, HEK93 cells were subjected to biotinylation with the presence and absence of p75NTR. Each samples were taken at different time points (0, 2, 5, and 15 mins), immunoblotted, and screened for the level of tyrosine-phosphorylated molecules. The result shows increases in the level of tyrosine-phosphorylated molecules with the presence of p75NTR. In absence of p75NTR, tyrosine-phosphorylated level fell below detection limitDetection limit
In analytical chemistry, the detection limit, lower limit of detection, or LOD , is the lowest quantity of a substance that can be distinguished from the absence of that substance within a stated confidence limit...
in 5 min. The biotinylated protein complex
Protein complex
A multiprotein complex is a group of two or more associated polypeptide chains. If the different polypeptide chains contain different protein domain, the resulting multiprotein complex can have multiple catalytic functions...
es were lysed to show both tyrosine-phosphorylated molecules in the surface and those that been internalized.
Precursor cell survival and proliferation
Numerous studies, both in vivoIn vivo
In vivo is experimentation using a whole, living organism as opposed to a partial or dead organism, or an in vitro controlled environment. Animal testing and clinical trials are two forms of in vivo research...
and in vitro
In vitro
In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...
, have shown that neurotrophins have proliferation and differentiation effects on CNS neuro-epithelial precursors, neural crest cells, or precursors of the enteric nervous system
Enteric nervous system
The enteric nervous system is a subdivision of the autonomic nervous system that directly controls the gastrointestinal system in vertebrates.It is derived from neural crest.-Function:...
. TrkA that expresses NGF not only increase the survival of both C and A delta classes of nocireceptor neurons, but also affect the functional properties of these neurons.4 As mentioned before, BDNF improves the survival and function of neurons in CNS, particularly cholinergic neurons of the basal forebrain
Basal forebrain
The basal forebrain is a collection of structures located ventrally to the striatum. It is considered to be the major cholinergic output of the central nervous system . It includes a group of structures that lie near the bottom of the front of the brain, including the nucleus basalis, diagonal band...
, as well as neurons in the hippocampus and cortex.
BDNF belongs to the neurotrophin family of growth factors and affects the survival and function of neurons in the central nervous system, particularly in brain regions susceptible to degeneration in AD. BDNF improves survival of cholinergic neurons of the basal forebrain, as well as neurons in the hippocampus and cortex.
TrkC that expresses NT3 has been shown to promote proliferation and survival of cultured 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....
cells, oligodendrocyte precursors, and differentiation of hippocampal neuron precursors.
Control of target innervation
Each of the neurotrophins mentioned above promotes neuriteNeurite
A neurite refers to any projection from the cell body of a neuron. This projection can be either an axon or a dendrite. The term is frequently used when speaking of immature or developing neurons, especially of cells in culture, because it can be difficult to tell axons from dendrites before...
outgrowth. NGF/TrkA signaling regulates the advance of sympathetic
Sympathetic nervous system
The sympathetic nervous system is one of the three parts of the autonomic nervous system, along with the enteric and parasympathetic systems. Its general action is to mobilize the body's nervous system fight-or-flight response...
neuron growth cones; even when neurons received adequate trophic (sustaining and nourishing) support, one experiment showed they did not grow into relating compartments without NGF. NGF increases the innervation of tissues that receive sympathetic or sensory innervation and induces aberrant innervation in tissues that are normally not innervated.
NGF/TrkA signaling upregulates BDNF, which is transported to both peripheral and central terminals of nocireceptive sensory neurons. In the periphery, TrkB/BDNF binding and TrkB/NT-4
NT-4
Neurotrophin-4 , also known as neurotrophin-5 , is a protein that in humans is encoded by the NTF4 gene.NT-4 is a neurotrophic factor that signals predominantly through the TrkB receptor tyrosine kinase....
binding acutely sensitizing nocireceptive pathway that require the presence of mast cell
Mast cell
A mast cell is a resident cell of several types of tissues and contains many granules rich in histamine and heparin...
s.
Sensory neuron function
Trk receptors and their ligands (neurotrophins) also affect neurons' functional properties. Both NT-3 and BDNF are important in the regulation and development of synapseSynapse
In the nervous system, a synapse is a structure that permits a neuron to pass an electrical or chemical signal to another cell...
s formed between afferent neurons and motor neuron
Motor neuron
In vertebrates, the term motor neuron classically applies to neurons located in the central nervous system that project their axons outside the CNS and directly or indirectly control muscles...
s. Increased NT-3/trkC binding results in larger monosynaptic
Reflex arc
A reflex arc is a neural pathway that controls an action reflex. In higher animals, most sensory neurons do not pass directly into the brain, but synapse in the spinal cord...
excitatory postsynaptic potential
Excitatory postsynaptic potential
In neuroscience, an excitatory postsynaptic potential is a temporary depolarization of postsynaptic membrane potential caused by the flow of positively charged ions into the postsynaptic cell as a result of opening of ligand-sensitive channels...
s (EPSPs) and reduced polysynaptic
Reflex arc
A reflex arc is a neural pathway that controls an action reflex. In higher animals, most sensory neurons do not pass directly into the brain, but synapse in the spinal cord...
components. On the other hand, increased NT-3 binding to trkB to BDNF has the opposite effect, reducing the size of monosynaptic excitatory postsynaptic potentials (EPSPs) and increasing polysynaptic signaling.
Formation of ocular dominance column
In the development of mammalian visual system, axons from each eyes crosses through the lateral geniculate nucleusLateral geniculate nucleus
The lateral geniculate nucleus is the primary relay center for visual information received from the retina of the eye. The LGN is found inside the thalamus of the brain....
(LGN) and terminate in separate layers of striate cortex
Visual cortex
The visual cortex of the brain is the part of the cerebral cortex responsible for processing visual information. It is located in the occipital lobe, in the back of the brain....
. However, axons from each LGN can only be driven by one side of the eye, but not both together. tThese axons that terminate in layer IV of the striate cortex result in ocular dominance
Ocular dominance
Ocular dominance, sometimes called eye dominance or eyedness, is the tendency to prefer visual input from one eye to the other. It is somewhat analogous to the laterality of right or left handedness; however, the side of the dominant eye and the dominant hand do not always match...
columns. A study shows that The density of innervating axons in layer IV from LGN can be increased by exogenous BDNF and reduced by a scavenger of endogenous BDNF. Therefore, it raises the possibility that both of these agents are involved in some sorting mechanism that is not well comprehended yet. Previous studies with cat model has shown that monocular deprivation
Monocular deprivation
Monocular deprivation is an experimental technique used by neuroscientists to study central nervous system plasticity. Generally, one of an animal's eyes is sutured shut during a period of high cortical plasticity...
occurs when input to one of the mammalian eyes is absent during the critical period (critical window). However, A study demonstrated that the infusion of NT-4 (a ligand of trkB) into the visual cortex during the critical period has been shown to prevent many consequences of monocular deprivation
Monocular deprivation
Monocular deprivation is an experimental technique used by neuroscientists to study central nervous system plasticity. Generally, one of an animal's eyes is sutured shut during a period of high cortical plasticity...
. Surprisingly, even after losing responses during the critical period, the infusion of NT-4 has been shown to be able to restore them.
Synaptic strength and plasticity
In mammalian hippocampusHippocampus
The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...
, the axons of the CA3 pyramidal cell
Pyramidal cell
Pyramidal neurons are a type of neuron found in areas of the brain including cerebral cortex, the hippocampus, and in the amygdala. Pyramidal neurons are the primary excitation units of the mammalian prefrontal cortex and the corticospinal tract. Pyramidal neurons were first discovered and...
s project into CA1 cells through the Schaffer collaterals. The long-term potentiation
Long-term potentiation
In neuroscience, long-term potentiation is a long-lasting enhancement in signal transmission between two neurons that results from stimulating them synchronously. It is one of several phenomena underlying synaptic plasticity, the ability of chemical synapses to change their strength...
(LTP) may induce in either of these pathways, but it is specific only to the one that is stimulated with tetanus
Tetanus
Tetanus is a medical condition characterized by a prolonged contraction of skeletal muscle fibers. The primary symptoms are caused by tetanospasmin, a neurotoxin produced by the Gram-positive, rod-shaped, obligate anaerobic bacterium Clostridium tetani...
. The stimulated axon does not impact spill over to the other pathway. TrkB receptors are expressed in most of these hippocampal neurons, including dentate
Dentate gyrus
The dentate gyrus is part of the hippocampal formation. It is thought to contribute to new memories as well as other functional roles. It is notable as being one of a select few brain structures currently known to have high rates of neurogenesis in adult rats, .The dentate gyrus cells receive...
granule cell
Granule cell
In neuroscience, granule cells refer to tiny neurons that are around 10 micrometres in diameter. Granule cells are found within the granular layer of the cerebellum , the dentate gyrus of the...
s, CA3 and CA1 pyramidal cells, and inhibitory interneurons. Interestingly, LTP can be greatly reduced by BDNF mutants. In a similar study on a mouse mutant with reduced expression of trkB receptors, LTP of CA1 cells reduced significantly. TrkB loss has also been linked to interfere with the memory acquisition and consolidation in many learning paradigm.
Activation pathway
Trk receptors dimerizeProtein dimer
In biochemistry, a dimer is a macromolecular complex formed by two, usually non-covalently bound, macromolecules like proteins or nucleic acids...
in response to ligand, as do other tyrosine kinase receptors. These dimers phosphorylate each other and enhance catalytic activity
Catalysis
Catalysis is the change in rate of a chemical reaction due to the participation of a substance called a catalyst. Unlike other reagents that participate in the chemical reaction, a catalyst is not consumed by the reaction itself. A catalyst may participate in multiple chemical transformations....
of the kinase. Trk receptors affect neuronal growth and differentiation through the activation of different signaling cascades. The three known pathways are PLC, Ras/MAPK (mitogen-activated protein kinase)
MAPK/ERK pathway
The MAPK/ERK pathway is a chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell. The signal starts when a growth factor binds to the receptor on the cell surface and ends when the DNA in the nucleus expresses a...
and the PI3K (phosphatidylinositol 3-kinase) pathways. These pathways involve the interception of nuclear and mitochondrial cell-death programs. These signaling cascades eventually led to the activation of a transcription factor
Transcription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...
, CREB
CREB
CREB is a cellular transcription factor. It binds to certain DNA sequences called cAMP response elements , thereby increasing or decreasing the transcription of the downstream genes....
(cAMP response element-binding), which in turn activate the target genes.
PKC pathways
The binding of neurotrophinNeurotrophin
Neurotrophins are a family of proteins that induce the survival, development, and function of neurons.They belong to a class of growth factors, secreted proteins that are capable of signaling particular cells to survive, differentiate, or grow. Growth factors such as neurotrophins that promote the...
will lead to the phosphorylation of phospholipase C
Phospholipase C
Phosphoinositide phospholipase C is a family of eukaryotic intracellular enzymes that play an important role in signal transduction processes. In general, this enzyme is denoted as Phospholipase C, although three other families of phospholipase C enzymes have been identified in bacteria and in...
(PLC) by trk receptor. This phosphorylation of PLC induces an enzyme to catalyze the breakdown of lipids to diacyglycerol and inositol(1,4, 5). Diacyglycerol may indirectly activate PI3 kinase or several protein kinase C
Protein kinase C
Protein kinase C also known as PKC is a family of enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and threonine amino acid residues on these proteins. PKC enzymes in turn are activated by signals such as increases in...
(PKC) isoforms, whereas inositol(1,4, 5) promotes release of calcium from intracellular stores.
Ras/MAPK pathway
The signaling through Ras/MAPK pathwayMAPK/ERK pathway
The MAPK/ERK pathway is a chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell. The signal starts when a growth factor binds to the receptor on the cell surface and ends when the DNA in the nucleus expresses a...
is important for the neurotrophin-induced differentiation of neuronal and neuroblastoma
Neuroblastoma
Neuroblastoma is the most common extracranial solid cancer in childhood and the most common cancer in infancy, with an annual incidence of about 650 cases per year in the US , and 100 cases per year in the UK . Close to 50 percent of neuroblastoma cases occur in children younger than two years old...
cells. Phosphorylation of tyrosine residues in the Trk receptors led to the activation of Ras molecules, H-Ras and K-Ras. H-ras is found in lipid raft
Lipid raft
The plasma membrane of cells is made of a combination of glycosphingolipids and protein receptors organized in glycolipoprotein microdomains termed lipid rafts...
s, embedded within 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...
, while K-Ras is predominantly found in disordered region of the membrane. RAP, a vesicle bounded molecule that also takes part in the cascading, is localized in the intracellular region.
The activation of these molecules result in two alternative MAP kinase
Mitogen-activated protein kinase
Mitogen-activated protein kinases are serine/threonine-specific protein kinases that respond to extracellular stimuli and regulate various cellular activities, such as gene expression, mitosis, differentiation, proliferation, and cell survival/apoptosis.-Activation:MAP kinases are activated...
pathways. Erk 1,2 can be stimulated through the activation cascades of K-Ras, Raf1, and MEK 1,2, whereas ERK5 is stimulated through the activation cascades of B-Raf, MEK5, and Erk 5. However, whether PKC (protein kinase C) could activate MEK5 is not yet known.
PI3 pathway
PI3 pathwayPI3K/AKT/mTOR pathway
The PI3K/AKT/mTOR pathway is an intracellular signalling pathway important in apoptosis and hence cancer e.g. breast cancerand non-small-cell lung cancer.]PI3K activation activates AKT which activates mTOR....
signaling is critical for both mediation of neurotrophin-induced survival and regulation of vesicular trafficking. The trk receptor stimulates P13 heterodimers, which causes the activation of kinases PDK-1 and Akt
AKT
Akt, also known as Protein Kinase B , is a serine/threonine protein kinase that plays a key role in multiple cellular processes such as glucose metabolism, cell proliferation, apoptosis, transcription and cell migration.-Family members:...
. Akt in turn stimulates FRK (Forkhead family transcription factor), BAD, and GSK-3
GSK-3
Glycogen synthase kinase 3 is a serine/threonine protein kinase that mediates the addition of phosphate molecules on certain serine and threonine amino acids in particular cellular substrates...
.