Neurotrophin

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. 

Huang EJ, Reichardt LF (2001) Neurotrophins roles in neuronal development and function. Annu Rev Neurosci 24 677-736... 

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. 

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... 

Neurotrophins are peptides or protein molecules that regulate both cell survival and cell death of specific neuronal phenotypes and thus serve to influence development, maintenance, function, and plasticity of the nervous system. 

Whether or not the production of /1-amyloid can be curtailed, it would be desirable to either replace the damaged neurons or encourage the remaining functional ones to ramify further and exhibit more influence. The former, which requires tissue or cell line grafts, is currently not feasible and barely investigated experimentally but there is much interest in the possible use of neurotrophic proteins (neurotrophins) that encourage neuronal growth and differentiation. 

Kaplan, D. R. and Miller, F. D., Signal transduction by the neurotrophin receptors, Curr. Opin. Cell. Biol., 9, 213-212, 1997. 

Berhow, M.T., Hiroi, N., Nestler, EJ. Regulation of ERK (extracellular signal regulated kinase), part of the neurotrophin signal transduction cascade, in the rat mesolimbic dopamine system by chronic exposure to morphine or cocaine. J. Neurosci. 16 4707, 1996. 

Pierce, R.C., Pierce-Bancroft, A.F., Prasad, B.M. Neurotrophin-3 contributes to the initiation of behavioral sensitization to cocaine by activating the Ras/Mitogen-activated protein kinase signal transduction cascade. J. Neurosci. 19 8685, 1999. 

Several independent laboratories have now demonstrated that both lithium and valproate (VPA) exert complex, isozyme-specific effects on the PKC (protein kinase C) signaling cascade (reviewed in [3, 5, 11-13]). Not surprisingly, considerable research has recently attempted to identify changes in the activity of transcription factors known to be regulated (at least in part) by the PKC signaling pathway - in particular the activator protein 1 (AP-1) family of transcription factors. In the CNS, the genes that are regulated by AP-1 include those for various neuropeptides, neurotrophins, receptors, transcription factors, enzymes involved in neurotransmitter synthesis, and proteins that bind to cytoskeletal elements [14]. 

Bronfman, F.C., Tcherpakov, M., Jovin, T.M., and Fainzilber, M. (2003) Ligand-induced internalization of the p75 neurotrophin receptor A slow route to the signaling endosome. J. Neurosci. 23(8), 3209-3220. 

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

Neurotrophic factors constitute a group of cytokines that regulate the development, maintenance and survival of neurons, both in the central and peripheral nervous systems (Table 10.12). Although the first member of this family (NGF) was discovered more than 50 years ago, it is only in the last decade that the other members have been identified and characterized. The major subfamily of neurotrophic factors is the neurotrophins. 

Inouye, A. and Sanes, J. R. Lamina-specific connectivity in the brain regulation by N-cadherin, neurotrophins, and glycoconjugates. Science 276 1428-1431,1997. 

Neurons constitute the most striking example of membrane polarization. A single neuron typically maintains thousands of discrete, functional microdomains, each with a distinctive protein complement, location and lifetime. Synaptic terminals are highly specialized for the vesicle cycling that underlies neurotransmitter release and neurotrophin uptake. The intracellular trafficking of a specialized type of transport vesicles in the presynaptic terminal, known as synaptic vesicles, underlies the ability of neurons to receive, process and transmit information. The axonal plasma membrane is specialized for transmission of the action potential, whereas the plasma... 

Extracellular ligands (hormones, neurotrophins, carrier protein, adhesion molecules, small molecules, etc.) will bind to specific transmembrane receptors. This binding of specific ligand induces the concentration of the receptor in coated pits and internalization via clathrin-coated vesicles. One of the best studied and characterized examples of RME is the internalization of cholesterol by mammalian cells [69]. In the nervous system, there are a plethora of different membrane receptors that bind extracellular molecules, including neurotrophins, hormones and other cell modulators, being the best studied examples. This type of clathrin-mediated endocytosis is an amazingly efficient process, capable of concentrating... 

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