Neurotrophin-3

Last updated
NTF3
Protein NTF3 PDB 1b8k.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases NTF3 , HDNF, NGF-2, NGF2, NT-3, NT3, neurotrophin 3
External IDs OMIM: 162660 MGI: 97380 HomoloGene: 1896 GeneCards: NTF3
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001102654
NM_002527

NM_001164034
NM_001164035
NM_008742

RefSeq (protein)

NP_001096124
NP_002518

NP_001157506
NP_001157507
NP_032768

Location (UCSC) Chr 12: 5.43 – 5.52 Mb Chr 6: 126.08 – 126.14 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Neurotrophin-3 is a protein that in humans is encoded by the NTF3 gene. [5] [6]

Contents

The protein encoded by this gene, NT-3, is a neurotrophic factor in the NGF (Nerve Growth Factor) family of neurotrophins. It is a protein growth factor which has activity on certain neurons of the peripheral and central nervous system; it helps to support the survival and differentiation of existing neurons, and encourages the growth and differentiation of new neurons and synapses. NT-3 was the third neurotrophic factor to be characterized, after nerve growth factor (NGF) and BDNF (Brain Derived Neurotrophic Factor). [7]

Function

Although the vast majority of neurons in the mammalian brain are formed prenatally, parts of the adult brain retain the ability to grow new neurons from neural stem cells; a process known as neurogenesis. Neurotrophins are chemicals that help to stimulate and control neurogenesis.

NT-3 is unique in the number of neurons it can potentially stimulate, given its ability to activate two of the receptor tyrosine kinase neurotrophin receptors (TrkC and TrkB). [8] [9]

Mice born without the ability to make NT-3 have loss of proprioceptive and subsets of mechanoreceptive sensory neurons. [10] [11]

Mechanism of action

NT-3 binds three receptors on the surface of cells which are capable of responding to this growth factor:

High affinity receptors

TrkC is a receptor tyrosine kinase (meaning it mediates its actions by causing the addition of phosphate molecules on certain tyrosines in the cell, activating cellular signaling).

As mentioned above, there are other related Trk receptors, TrkA and TrkB. Also as mentioned, there are other neurotrophic factors structurally related to NT-3:

While TrkB mediates the effects of BDNF, NT-4, and NT-3, TrkA binds and is activated by NGF, and TrkC binds and is activated only by NT-3.

Low affinity receptors

The other NT-3 receptor, the LNGFR, plays a somewhat less clear role. Some researchers have shown the LNGFR binds and serves as a "sink" for neurotrophins.

The crystal structure of NT-3 shows that NT-3 forms a central homodimer around which two glycosylated p75 LNGFR molecules bind symmetrically. The symmetrical binding takes place along the NT-3 interfaces, resulting in a 2:2 ligand-receptor cluster in the center. [15]

Cells which express both the LNGFR and the Trk receptors might therefore have a greater activity – since they have a higher "microconcentration" of the neurotrophin.

It has also been shown, however, that the LNGFR may signal a cell to die via apoptosis – so therefore cells expressing the LNGFR in the absence of Trk receptors may die rather than live in the presence of a neurotrophin.

See also

Related Research Articles

A growth factor is a naturally occurring substance capable of stimulating cell proliferation, wound healing, and occasionally cellular differentiation. Usually it is a secreted protein or a steroid hormone. Growth factors are important for regulating a variety of cellular processes.

<span class="mw-page-title-main">Brain-derived neurotrophic factor</span> Protein

Brain-derived neurotrophic factor (BDNF), or abrineurin, 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), a family which also includes NT-3 and NT-4/NT-5. Neurotrophic factors are found in the brain and the periphery. BDNF was first isolated from a pig brain in 1982 by Yves-Alain Barde and Hans Thoenen.

<span class="mw-page-title-main">Neurotrophin</span>

Neurotrophins are a family of proteins that induce the survival, development, and function of neurons.

<span class="mw-page-title-main">Nerve growth factor</span> Mammalian protein found in Homo sapiens

Nerve growth factor (NGF) is a neurotrophic factor and neuropeptide primarily involved in the regulation of growth, maintenance, proliferation, and survival of certain target neurons. It is perhaps the prototypical growth factor, in that it was one of the first to be described. Since it was first isolated by Nobel Laureates Rita Levi-Montalcini and Stanley Cohen in 1956, numerous biological processes involving NGF have been identified, two of them being the survival of pancreatic beta cells and the regulation of the immune system.

George D. Yancopoulos is a Greek-American biomedical scientist who is the co-founder, president and chief scientific officer of Regeneron Pharmaceuticals.

<span class="mw-page-title-main">Tropomyosin receptor kinase A</span> Protein-coding gene in the species Homo sapiens

Tropomyosin receptor kinase A (TrkA), also known as high affinity nerve growth factor receptor, neurotrophic tyrosine kinase receptor type 1, or TRK1-transforming tyrosine kinase protein is a protein that in humans is encoded by the NTRK1 gene.

<span class="mw-page-title-main">Tropomyosin receptor kinase B</span> Protein and coding gene in humans

Tropomyosin receptor kinase B (TrkB), also known as tyrosine receptor kinase B, 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. TrkB is a receptor for brain-derived neurotrophic factor (BDNF). Standard pronunciation is "track bee".

<span class="mw-page-title-main">Low-affinity nerve growth factor receptor</span> Human protein-coding gene

The p75 neurotrophin receptor (p75NTR) was first identified in 1973 as the low-affinity nerve growth factor receptor (LNGFR) before discovery that p75NTR bound other neurotrophins equally well as nerve growth factor. p75NTR is a neurotrophic factor receptor. Neurotrophic factor receptors bind Neurotrophins including Nerve growth factor, Neurotrophin-3, Brain-derived neurotrophic factor, and Neurotrophin-4. All neurotrophins bind to p75NTR. This also includes the immature pro-neurotrophin forms. Neurotrophic factor receptors, including p75NTR, are responsible for ensuring a proper density to target ratio of developing neurons, refining broader maps in development into precise connections. p75NTR is involved in pathways that promote neuronal survival and neuronal death.

<span class="mw-page-title-main">Tropomyosin receptor kinase C</span>

Tropomyosin receptor kinase C (TrkC), also known as NT-3 growth factor receptor, neurotrophic tyrosine kinase receptor type 3, or TrkC tyrosine kinase is a protein that in humans is encoded by the NTRK3 gene.

Neurotrophic factors (NTFs) are a family of biomolecules – nearly all of which are peptides or small proteins – that support the growth, survival, and differentiation of both developing and mature neurons. Most NTFs exert their trophic effects on neurons by signaling through tyrosine kinases, usually a receptor tyrosine kinase. In the mature nervous system, they promote neuronal survival, induce synaptic plasticity, and modulate the formation of long-term memories. Neurotrophic factors also promote the initial growth and development of neurons in the central nervous system and peripheral nervous system, and they are capable of regrowing damaged neurons in test tubes and animal models. Some neurotrophic factors are also released by the target tissue in order to guide the growth of developing axons. Most neurotrophic factors belong to one of three families: (1) neurotrophins, (2) glial cell-line derived neurotrophic factor family ligands (GFLs), and (3) neuropoietic cytokines. Each family has its own distinct cell signaling mechanisms, although the cellular responses elicited often do overlap.

<span class="mw-page-title-main">Ciliary neurotrophic factor</span>

Ciliary neurotrophic factor is a protein that in humans is encoded by the CNTF gene.

<span class="mw-page-title-main">Neurotrophin-4</span> Protein-coding gene in the species Homo sapiens

Neurotrophin-4 (NT-4), also known as neurotrophin-5 (NT-5), is a protein that in humans is encoded by the NTF4 gene. It is a neurotrophic factor that signals predominantly through the TrkB receptor tyrosine kinase.

<span class="mw-page-title-main">Nerve injury</span> Damage to nervous tissue

Nerve injury is an injury to nervous tissue. There is no single classification system that can describe all the many variations of nerve injuries. In 1941, Seddon introduced a classification of nerve injuries based on three main types of nerve fiber injury and whether there is continuity of the nerve. Usually, however, peripheral nerve injuries are classified in five stages, based on the extent of damage to both the nerve and the surrounding connective tissue, since supporting glial cells may be involved.

Trk receptors are a family of tyrosine kinases that regulates synaptic strength and plasticity in the mammalian nervous system. Trk receptors affect neuronal survival and differentiation through several signaling cascades. However, the activation of these receptors also has significant effects on functional properties of neurons.

<span class="mw-page-title-main">VGF</span>

VGF or VGF nerve growth factor inducible is a secreted protein and neuropeptide precursor that may play a role in regulating energy homeostasis, metabolism and synaptic plasticity. The protein was first discovered in 1985 by Levi et al. in an experiment with PC12 cells and its name is non-acronymic. VGF gene encodes a precursor which is divided by proteolysis to polypeptides of different mass, which have a variety of functions, the best studied of which are the roles of TLQP-21 in the control of appetite and inflammation, and TLQP-62 as well as AQEE-30 in regulating depression-like behaviors and memory. The expression of VGF and VGF-derived peptides is detected in a subset of neurons in the central and peripheral nervous systems and specific populations of endocrine cells in the adenohypophysis, adrenal medulla, gastrointestinal tract, and pancreas. VGF expression is induced by NGF, CREB and BDNF and regulated by neurotrophin-3. Physical exercise significantly increases VGF expression in mice hippocampal tissue and upregulates a neurotrophic signaling cascade thought to underlie the action of antidepressants.

Neurotrophic factor receptors or neurotrophin receptors are a group of growth factor receptors which specifically bind to neurotrophins.

<span class="mw-page-title-main">BNN-20</span>

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<span class="mw-page-title-main">BNN-27</span> Chemical compound

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Lorne Mendell is a neurobiologist currently employed as a distinguished professor in the department of neurobiology and behavior at Stony Brook University in New York. His research focuses primarily on neurotrophins in neonatal and adult mammals, and on the neuroplasticity of the mammalian spinal cord. His research interests lie in other areas including pain, nerve wind-up, and specifically the neurotrophin NT-3. He has contributed to the growing pool of knowledge of axonal development and regeneration of immature and mature neurons. He has been a part of the search for novel treatments for spinal cord injuries and continues to study neurotrophins to determine their effects on neuronal plasticity. He served a term as president of the Society of Neuroscience during 1997–1998.

Neurotrophin mimetics are small molecules or peptide like moleculess that can modulate the action of the neurotrophin receptor. One of the main causes of neurodegeneration involves changes in the expression of neurotrophins (NTs) and/or their receptors. Indeed, these imbalances or changes in their activity, lead to neuronal damage resulting in neurological and neurodegenerative conditions. The therapeutic properties of neurotrophins attracted the focus of many researchers during the years, but the poor pharmacokinetic properties, such as reduced bioavailability and low metabolic stability, the hyperalgesia, the inability to penetrate the blood–brain barrier and the short half-lives render the large neurotrophin proteins not suitable to be implemented as drugs.

References

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Further reading