Neurotrophin
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Neurotrophins, are a family of proteins that induce the survival of neurons. They belong to a class of growth factors, secreted proteins, which 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 - thus allowing the neurons to survive. Neurotrophins also induce differentiation of progenitor cells, to form neurons. Some scientists employ the term "neurotrophin" as a synonym for "neurotrophic factor", while most reserve the term "neurotrophin" for four structurally related factors -nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4). Another neurotrophic factor, known as novel neurotrophin-1 (NNT1) is structurally unrelated to NGF, BDNF, NT-3 and NT-4.
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[edit] Receptors
There are two classes of receptors, p75 and the "Trk" family of Tyrosine kinases receptors.
- p75 is a low affinity neurotrophin receptor, to which all neurotrophins bind. It is a member of the tumour necrosis super family.
- The Trk family include TrkA, TrkB, and TrkC, and will only bind with specific neurotrophins, but with a much higher affinity. The Trks mediate the functional signals of the neurotrophins.
- NGF binds to TrkA, BDNF and NT-4 bind to TrkB and NT-3 binds to TrkC. In addition NT-3 also binds to and activates TrkA and TrkB but it does so less efficiently.
- Whilst the Trk receptors have a clearly defined trophic role, p75 receptors activate signalling pathways which can also result in apoptosis.
[edit] Nerve growth factor
Nerve growth factor (NGF), the prototypical growth factor, is a protein secreted by a neuron's target. NGF is critical for the survival and maintenance of sympathetic and sensory neurons. NGF is released from the target cells, binds to and activates its high affinity receptor TrkA, and is internalized into the responsive neuron. The NGF/TrkA complex is subsequently trafficked back to the cell body. This movement of NGF from axon tip to soma is thought to be involved in the long-distance signaling of neurons[citation needed].
[edit] Brain-derived neurotrophic factor
Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor found originally in the brain, but also found in the periphery. More specifically, it is a protein which has activity on certain neurons of the central nervous system and the peripheral nervous system; it helps to support the survival of existing neurons, and encourage the growth and differentiation of new neurons and synapses through axonal and dendritic sprouting. In the brain, it is active in the hippocampus, cortex, cerebellum, and basal forebrain—areas vital to learning, memory, and higher thinking. BDNF was the second neurotrophic factor to be characterized, after NGF and before neurotrophin-3.
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, BDNF being one of the most active. 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.
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.
[edit] Novel Neurotrophin-1
Novel Neurotrophin-1 (NNT-1) is also known as "B cell-stimulating factor-3" (BSF-3) or "cardiotrophin-like cytokine factor 1" (CLCF1), and is a cytokine belonging to the interleukin-6 family. It is a secreted protein, found predominantly in lymph nodes and spleen, which contains 225 amino acids with a molecular mass of 22 kDa in its mature form. It is closely related to other proteins called cardiotrophin-1 and ciliary neurotrophic factor. The term "neurotrophin" is commonly used to refer collectively to the four structurally related factors NGF, BDNF, NT-3 and NT-4, while NNT1 bears no structural resemblance to these four proteins. The terminology has become confusing since most scientists use the term "neurotrophin" to refer only to NGF, BDNF, NT-3 and NT-4, while a few scientists use the term "neurotrophin" to refer to any neurotrophic factor, of which there are many.
NNT-1/BSF-3 induces tyrosine phosphorylation of the IL-6 receptor common subunit glycoprotein 130 (gp130), leukemia inhibitory factor receptor beta, and the transcription factor STAT3. It has been implicated in the induction of IL-1 (via induction of corticosterone and IL-6) and serum amyloid A, and in B cell hyperplasia. This cytokine is capable of B cell activation via gp130 receptor stimulation.[1]
[edit] Neurotrophin-3
Neurotrophin-3, or NT-3, is a neurotrophic factor, in the NGF-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 NGF and BDNF.
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 - see below). Mice born without the ability to make NT-3 have loss of proprioceptive and subsets of mechanoreceptive sensory neurons. Interestingly, anti-depressant drugs produce behavioural changes mainly through gradual effect on BDNF and desensitisement of autoreceptors.
[edit] Neurotrophin-4
Neurotrophin-4 (NT-4) like BDNF, is a neurotrophic factor that signals predominantly through the TrkB receptor tyrosine kinase. It is also known as NT4, NT5, NTF4, and NT-4/5.[2]
[edit] References
- ^ Senaldi et al., Novel neurotrophin-1/B cell-stimulating factor-3: a cytokine of the IL-6 family. Proc Natl Acad Sci U S A. 1999 September 28;96(20):11458-63
- ^ Entrez database entry for NT-4/5. NCBI. Retrieved on 2007-05-07.
- Arévalo J, Wu S (2006). "Neurotrophin signaling: many exciting surprises!". Cell Mol Life Sci 63 (13): 1523-37. doi:. PMID 16699811.
- Hempstead B (2006). "Dissecting the diverse actions of pro- and mature neurotrophins". Curr Alzheimer Res 3 (1): 19-24. doi:. PMID 16472198.
- Allen S, Dawbarn D (2006). "Clinical relevance of the neurotrophins and their receptors". Clin Sci (Lond) 110 (2): 175-91. PMID 16411894.
[edit] 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 (July 5, 2006)
- Helsinki.fi - 'Neurotrophic factors'
- MeSH Neurotrophins
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