BDNF, neurotrophin

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 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 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). 

Neurotropic factors of dopaminergic neurons may represent a potential neuroprotective therapy for Parkinson s disease. Apart from nerve growth factor (NGF), the family of the neurotrophins subsumes at the present time BDNF, neurotrophin-3 (NT-3), and neurotrophin-4/5 (NT-4/5). However, the concept of neurotrophic factors as specific, target-derived molecules, each acting on distinct neuronal types, has to be modified because of their high degree of pleiotropism and a... 

The neurotrophin receptor p75 was first identified as a nerve growth factor (NGF)-binding protein and was subsequently shown to interact with each of the other neurotrophic factors, BDNF, neurotrophin-3, and neurotrophin-4/-5. It also modulates the activity of several members of the tropomyosin-related receptor tyrosine kinase family (Trk) (reviewed in Chao, 2003). p75, a member of the tumor necrosis factor superfamily, is a type I transmembrane protein with four cysteine-rich domains in its extracellular region and a Death domain in its cytoplasmic protein (Fig. 11). 

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. 

The continued availability of adequate trophic support appears to be crucial not only for the development of nerve cells and their interconnecting circuitry, but also for the maintenance of neurons and their synapses in the adult (31). There is considerable evidence that diffusible, target-derived trophic factors play important roles in the development of specific retinal cell types. In particular, the neurotrophins [nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin (NT)-3 and NT-4/5] have received considerable attention for their potential roles in both developing and adult nervous systems (66,67). 

Neurotrophins are a family of related proteins that contain the following family members nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and NT-4/5. All neurotrophins are synthesized as proforms that are cleaved to release the active, mature forms. Each neurotrophin binds with high affinity to one of the tyrosine receptor kinase (trk) family of transmembrane receptors NGF to trkA, BDNF and NT-4/5 to trkB and NT-3 to trkC. The neurotrophins all act on trks that are expressed on sensory nerve terminals, the end result being enhanced sensitivity of the nociceptors. The two neurotrophins that have been most intimately linked to both injury-induced nociceptive and neuropathic pain are NGF and BDNF. 

---