Neurotrophin
Encyclopedia
Neurotrophins are a family of protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

s that induce the survival, development, and function of neurons.

They belong to a class of growth factors, secreted
Exocytosis
Exocytosis , also known as 'The peni-cytosis', is the durable process by which a cell directs the contents of secretory vesicles out of the cell membrane...

 proteins that are capable of signaling particular cells to survive, differentiate, or grow. Growth factors such as neurotrophins that promote the survival of neurons are known as neurotrophic factors. Neurotrophic factors are secreted by target tissue and act by preventing the associated neuron from initiating programmed cell death
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...

 - thus allowing the neurons to survive. Neurotrophins also induce differentiation of progenitor cells, to form neurons.

Although the vast majority of neurons in the mammal
Mammal
Mammals are members of a class of air-breathing vertebrate animals characterised by the possession of endothermy, hair, three middle ear bones, and mammary glands functional in mothers with young...

ian 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,...

 are formed prenatally, parts of the adult brain (for example, the hippocampus
Hippocampus
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...

) retain the ability to grow new neurons from neural stem cell
Stem cell
This article is about the cell type. For the medical therapy, see Stem Cell TreatmentsStem cells are biological cells found in all multicellular organisms, that can divide and differentiate into diverse specialized cell types and can self-renew to produce more stem cells...

s, a process known as neurogenesis
Neurogenesis
Neurogenesis is the process by which neurons are generated from neural stem and progenitor cells. Most active during pre-natal development, neurogenesis is responsible for populating the growing brain with neurons. Recently neurogenesis was shown to continue in several small parts of the brain of...

. Neurotrophins are chemicals that help to stimulate and control neurogenesis.

Terminology

The term neurotrophin may be used as a synonym for neurotrophic factor, but the term neurotrophin is more generally reserved for four structurally related factors: 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), 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), neurotrophin-3
Neurotrophin-3
Neurotrophin-3 is a protein that in humans is encoded by the NTF3 gene.The protein encoded by this gene, NT-3, is a neurotrophic factor in the NGF family of neurotrophins...

 (NT-3), and neurotrophin-4 (NT-4), with neurotrophic factor additionally referring to the GDNF family of ligands
GDNF family of ligands
The GDNF family of ligands consists of four neurotrophic factors: glial cell line-derived neurotrophic factor , neurturin , artemin , and persephin . GFLs have been shown to play a role in a number of biological processes including cell survival, neurite outgrowth, cell differentiation and cell...

 and ciliary neurotrophic factor
Ciliary neurotrophic factor
Ciliary neurotrophic factor is a protein that in humans is encoded by the CNTF gene.CNTF has also been shown to be expressed by cells on the bone surface, and to reduce the activity of bone forming cells, osteoblasts.- Satiety effects :...

 (CNTF).

Function

During the development of the vertebrate nervous system, many neurons become redundant (because they have died, failed to connect to target cells, etc.) and are eliminated. At the same time, developing neurons send out 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....

 outgrowths that contact their target cells. Such cells control their degree of innervation (the number of axon connections) by the secretion of various specific neurotrophic factors that are essential for neuron survival. One of these is 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 or beta-NGF), a vertebrate protein that stimulates division and differentiation of sympathetic and embryonic sensory neurons. NGF is mostly found outside the central nervous system (CNS), but slight traces have been detected in adult CNS tissues, although a physiological role for this is unknown. It has also been found in several snake venoms.

In the peripheral and central neurons, neurotrophins are important regulators for suvival, differentiation, and maintenance of nerve cells. They are small proteins that secrete into the nervous system to help keep nerve cells alive. There are two distinct classes of glycosylated receptors that can bind to neurotrophins. These two proteins are p75 (NTR), which binds to all neurotrophins, and subtypes of Trk, which are only specific for each different neurotrophins. The reported structure above is a 2.6 Å-resolution crystal structure of neurotrophin-3 (NT-3) complex to the ectodomain of glycosylated p75 (NRT), forming a symmetrical crystal structure. This is different to other studies which shows a dimer of nerve growth factor (NGF) bound to a single ectodomain of deglycosylated p75(NTR), resulting in an asymmetrical crystal structure. The crystal structure of NT-3 shows that NT-3 forms a central homodimer around which two glycosylated p75 (NRT) molecules bind symmetrically. The symmetrical binding takes place along the NT-3 interfaces, resulting in a 2:2 ligand-receptor cluster in the center. The symmetrical and asymmetrical structures show that there is a significant difference in ligand-receptor interactions and p75 (NRT) conformations. This symmetrical complex indicates that p75(NRT) activates at the cell surface. In addition, this symmetrical crystal structure provides a model for NTs-p75(NTR) recognition and signal generation, as well as insights into coordination between p75(NTR) and Trks.

Structure

NGF is a protein of about 120 residues that is cleaved from a larger precursor molecule. It contains six cysteines all involved in intrachain disulfide bond
Disulfide bond
In chemistry, a disulfide bond is a covalent bond, usually derived by the coupling of two thiol groups. The linkage is also called an SS-bond or disulfide bridge. The overall connectivity is therefore R-S-S-R. The terminology is widely used in biochemistry...

s. A schematic representation of the structure of NGF is shown below:
+------------------------+
| |
| |
xxxxxxCxxxxxxxxxxxxxxxxxxxxxCxxxxCxxxxxCxxxxxxxxxxxxxCxCxxxx
| | | |
+--------------------------|-----+ |
+---------------------+

where 'C': conserved cysteine involved in a disulfide bond.

Receptors


There are two classes of 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...

s for neurotrophins: p75 and the "Trk" family of Tyrosine kinase
Tyrosine kinase
A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a protein in a cell. It functions as an "on" or "off" switch in many cellular functions....

s receptors.

Nerve growth factor

Nerve growth factor (NGF), the prototypical 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....

, is a protein secreted by a neuron's target cell
Target cell
-Hematology:In hematology, target cells are very abnormal red blood cells, that have a bullseye appearance . These target cells are associated with Hemoglobin C disease, Asplenia, Liver Disease, Thalassemia and severe Iron deficiency anemia...

. NGF is critical for the survival and maintenance 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...

 and sensory
Sensory neuron
Sensory neurons are typically classified as the neurons responsible for converting external stimuli from the environment into internal stimuli. They are activated by sensory input , and send projections into the central nervous system that convey sensory information to the brain or spinal cord...

 neurons. NGF is released from the target cells, binds to and activates its high affinity receptor 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....

 on the neuron, and is internalized into the responsive neuron. The NGF/TrkA complex is subsequently trafficked back to the neuron's cell body
Soma (biology)
The soma , or perikaryon , or cyton, is the bulbous end of a neuron, containing the cell nucleus. The word "soma" comes from the Greek σῶμα, meaning "body"; the soma of a neuron is often called the "cell body"...

. This movement of NGF from 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....

 tip to soma
Soma (biology)
The soma , or perikaryon , or cyton, is the bulbous end of a neuron, containing the cell nucleus. The word "soma" comes from the Greek σῶμα, meaning "body"; the soma of a neuron is often called the "cell body"...

 is thought to be involved in the long-distance signaling of neurons.

Brain-derived neurotrophic factor

Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor found originally in 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,...

, but also found in the periphery. To be specific, it is a protein that has activity on certain neurons of 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...

 and the peripheral nervous system; it helps to support the survival of existing neurons, and encourage the growth and differentiation of new neurons and 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 through axonal and dendritic
Dendrite
Dendrites are the branched projections of a neuron that act to conduct the electrochemical stimulation received from other neural cells to the cell body, or soma, of the neuron from which the dendrites project...

 sprouting. In the brain, it is active in the hippocampus
Hippocampus
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...

, cortex
Cerebral cortex
The cerebral cortex is a sheet of neural tissue that is outermost to the cerebrum of the mammalian brain. It plays a key role in memory, attention, perceptual awareness, thought, language, and consciousness. It is constituted of up to six horizontal layers, each of which has a different...

, cerebellum
Cerebellum
The cerebellum is a region of the brain that plays an important role in motor control. It may also be involved in some cognitive functions such as attention and language, and in regulating fear and pleasure responses, but its movement-related functions are the most solidly established...

, and basal forebrain — areas vital to learning, memory, and higher thinking. BDNF is the second neurotrophic factor to be characterized, after NGF and before neurotrophin-3.

BDNF is one of the most active substances to stimulate neurogenesis. Mice born without the ability to make BDNF suffer developmental defects in the brain and sensory nervous system, and usually die soon after birth, suggesting that BDNF plays an important role in normal neural 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...

.

Despite its name, BDNF is actually found in a range of tissue and cell types, not just the brain. Expression can be seen in the retina, the CNS, motor neurons, the kidneys, and the prostate.

Neurotrophin-3

Neurotrophin-3, or NT-3, is a neurotrophic factor, in the NGF-family of neurotrophins. It is a protein growth factor that has activity on certain neurons of the peripheral and 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...

; it helps to support the survival and differentiation of existing neurons, and encourages the growth and differentiation of new neurons and 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. NT-3 is the third neurotrophic factor to be characterized, after NGF and BDNF.

NT-3 is unique among the neurotrophins in the number of neurons it has potential to stimulate, given its ability to activate two of the receptor tyrosine kinase neurotrophin receptors (TrkC
TrkC
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....

 and TrkB
TrkB
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:...

). Mice born without the ability to make NT-3  have loss of proprioceptive and subsets of mechanoreceptive sensory neurons.

Neurotrophin-4

Neurotrophin-4 (NT-4) is a neurotrophic factor that signals predominantly through the TrkB
TrkB
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:...

 receptor tyrosine kinase
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....

. It is also known as NT4, NT5, NTF4, and NT-4/5.

External links

  • DevBio.com - 'Neurotrophin Receptors: The neurotrophin family consists of four members: nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT-3), and neurotrophin 4 (NT-4)' (April 4, 2003)
  • Dr.Koop.com - 'New Clues to Neurological Diseases Discovered: Findings could lead to new treatments, two studies suggest', Steven Reinberg, HealthDay
    HealthDay
    HealthDay's health news service is a division of ScoutNews, LLC, a private company founded in 2001 and based in Norwalk, Connecticut.HealthDay specializes in producing and licensing daily health news on the Internet for and The company's custom content division provides customized health articles...

    (July 5, 2006)
  • Helsinki.fi - 'Neurotrophic factors'
  • http://www.rcsb.org/pdb/explore/explore.do?structureId=3BUK - Neurotrophin-3 image
The source of this article is wikipedia, the free encyclopedia.  The text of this article is licensed under the GFDL.
 
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