Neurotrophin NGF/BDNF

Anterograde motor (kinesin) Retrograde motor (dynein) Neurotrophin (NGF, BDNF, etc.) Trk receptor Anterograde vesicle Lysosome... 

The major biological role of OL is myelination. However, OL may also promote neuronal survival, axonal growth and process formation. Neuronal function is also influenced by OL-derived soluble factors that induce sodium channelclustering along axons. Neurotrophins (NGF, BDNF, and NTS) produced from OL may provide the trophic support for both OL and local neurons. 

Bcl-2 expression prevents or delays apoptosis under a variety of circumstances. These include (a) withdrawal of the neurotrophins NGF, BDNF, and NT-3 from primary neuron cultures and from PC 12 cells (Garcia et al., 1992 Allsopp et al., 1993 Mah et al., 1993), (b) induction of apoptosis in thymocytes by glucocorticoids, irradiation, anti CD3-Ab (anti-TCR ab) and Ca + ionophores (Sentman et al., 1991 Siegal et al., 1992), (c) some models of AICD (Strasser et al., 1991 Siegal et al., 1992) and (d) withdrawal of growth factor from IL-3-and IL-4-or GM-CSF-dependent haematopoietic cell lines (Vaux et al., 1988 Nunez et al., 1990). 

Neurotrophins (NGF brain-derived neurotrophic factor, BDNF neurotrophin-3, NT-3 NT-4 NT-6) are important regulators of neural survival, development, function, and plasticity of the vertebrate nervous system [1]. Neurotrophins generally function as noncovalently associated homodimers. They activate two different classes of receptors, through which signaling pathways can be activated, including those mediated by Ras and members of the cdc42/rac/rho G protein families, MAP kinase, PI-3 kinase, and Jun kinase cascades. 

The neurotrophins (NGF, brain-derived neurotrophic factor (BDNF), NT-3, NT-4/5)... 

Such an approach could be underpinned by the development of engineered proteins displaying multiple neurotrophic activities. Pan-neurotrophin-1, for example, is an engineered chimaeric neurotrophin, containing the active domains of NGF, BDNF and NT-3. This hybrid molecule can bind the neurotrophin receptors Trk A, B and C, as well as P75. 

Figure 3.5 Schematic workflow of sample preparation for 2D-DIGE. SYSY-TrkA and SYSY-TrkB cells were stimulated by neurotrophins NGF (100 ng/mL) or BDNF (50 ng/mL), respectively ( treated cells ). Controls received fresh medium without neurotrophins att = 0 ( untreated cells ). Samples of the same time point following...

There is now strong evidence that two neurotrophins, NGF and BDNF act as important mediators and modulators of pain in a variety of circumstances. Particularly, NGF can promote the sensitization and activation of nociceptors (Pezet... 

The neurotrophin family includes NGF, BDNF, neurotrophin-3 (NT-3), NT-4/5, and NT-6. All neurotrophins are capable of binding to the p75 receptor each neurotrophin also binds to a specific Trk receptor. Trk is the receptor for NGF TrkB is the receptor for BDNF and NT-4, while TrkC is the receptor for NT-3. Neurotrophins secreted by cells protect neurons from apoptosis (Korsching, 1993 Lewin and Barde, 1996). Similarly, ciliary neurotrophic factor (CNTF), a structurally related type I cytokine and GDNF, structurally related to TGF-[3, each constitute a sub-family of neurotrophic factors. 

In recent studies from Davies laboratory (Wright et al., 1993), it has been proposed that BDNF or neurotrophin-3 (NT-3) acts at the stage after neuronal differentiation, but before the neurons become dependent on NGF. BDNF or NT-3 accelerate the maturation of neurons before they become dependent on neurotrophic factors for survival, but the maturation process can still occur in the absence of these factors. 

The relationship between the two receptors for NGF is complex and not yet completely understood. It has been suggested that the functional form of the NGF receptor is a heterodimer of p75 and pl40 proteins. BDNF and NT-3 bind to p75, but the functional receptors for these neurotrophins are the proto-oncogene products of and trkQ. 

NGF binds to the transmembrane receptor tyrosine kinase (trk, or pl40trk), now referred to as TrkA. BDNF binds to TrkB, whereas NT-3 can bind to all three Trk (A,B,C) receptors, with a preference to TrkC, and NT-4/ 5 can bind both TrkA and TrkB. Furthermore, all neurotrophins also bind with equal affnity to a 75 kD transmembrane glycoprotein, p75NTR (also referred to... 

The neurotrophins comprise a family of highly related molecules that act to support the survival and phenotypic specificity of select subsets of neurons. The neurotrophins (Table 27-2) are small highly basic proteins of approximately 13kDa that dimerize to form the biologically active species [5]. The neurotrophins have a highly conserved structure. This family includes five distinct members NGF,brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), neurotrophin 4/5 (NT4/5) and neurotrophin 6 (NT6). NT6 is found only in fish and will not be discussed further. 

The neurotrophins interact with two distinct cell surface receptor species [5,6,9] (Fig. 27-2). The neurotrophins bind to the Trk family of receptors, which serve as the principal signal transducer for this class of growth factors. The Trk receptors comprise a small, highly related family of molecules that possess an extracellular ligand binding domain that selectively interacts with the individual neurotrophin species. Trk A specifically binds NGF, TrkB interacts with BDNF and NT4/5, and TrkC preferentially binds NT3. Importantly, the Trk receptors have an intracellular tyrosine kinase domain that is activated upon neurotrophin binding. The kinase domains of the Trk family members are highly conserved and the Trks differ mainly in the structure of their extracellular domains. Trk receptor expression is limited to neurons and the... 

FIGURE 2 7-2 Neurotrophin receptors. Neurotrophin family members bind specifically to cognate Trk receptors. The low affinity neurotrophin receptor, p75, promiscuously binds all neurotrophins. BDNF, brain-derived neurotrophic factor NGF, nerve growth factor NT, neurotrophin. 

The neurotrophins are a group of neurotrophic factors which all belong to the same gene family. They include NGF, as well as brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin 4/5 (NT-4/5) and neurotrophin-6 (NT-6). All are small, basic proteins sharing approximately 50% amino acid homology. They exist mainly as homodimers and promote signal transduction by binding to a member of the Trk family of tyrosine kinase receptors (Table 7.10). 

The synthesis of oligonucleotide primers, based upon conserved sequences between the NGF and BDNF genes, allowed researchers to fish for additional members of the neurotrophin family by PCR analysis. In 1991 this led to the discovery of neurotrophin 3 (NT-3), which is expressed early in — and throughout — embryogenesis. It supports the development of various neuronal populations in culture, although its role in vivo is less well understood. 

The signaling mechanisms activated by neurotrophic factors, which include nerve growth factor (NGF), brain derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) are fundamentally different from those discussed for G protein-coupled receptors and Ca " (Russell and Duman 2002). The neurotrophic factors bind to specific receptors, TrkA, TrkB, and TrkC (the name Trk is derived from their identification as troponin/receptor kinases from colon carcinoma) (Fig. 2). The Trk receptors contain an extracellular binding domain, a transmembrane domain, and an intracellular tyrosine kinase domain. Two neurotrophic factor molecules are required for activation of a Trk receptor dimer, resulting in activation of the tyrosine kinase domains and phosphorylation of substrate proteins as well as autophosphorylation of the Trk receptor itself. 

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