Neurotrophin receptors

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 role of neurotrophins in the pathogenesis of allergic disease and asthma has been appreciated only recently. Neurotrophins are a family of growth factors that have common receptors and physiologic effects and are the principal regulators of neuronal activity, differentiation and maintenance. In humans, there are at least four defined neurotrophins also termed NGFs. These polypeptides include NGF, neurotrophin 3 (NT-3), neurotrophin 4/5 (NT-4/5) and brain-derived neurotrophic factor (BDNF). They all act on a common group of tropomyosin-related tyrosine kinase (Trk) receptors. Neurotrophin receptors are expressed in the neurons of both the central and peripheral nervous systems. 

Neurotrophin Receptors Neurotrophins bind to and activate a family of receptor tyrosine kinases called Trks (pronounced tracks ). (The general structure of receptor tyrosine kinases and the Intracellular signaling pathways they activate are covered In Chapter 14.) As shown In Figure 22-28, NGF binds to TrkA BDNF, to TrkB and NT-3, to TrkC. Binding of these factors to their receptors provides a survival signal for different classes of neurons. A second type of receptor called (NTR = neurotrophin receptor) also binds to neurotrophins, but with lower affinity. However, forms heteromulti-... 

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. 

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... 

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

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. 

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... 

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

Patapoutian, A. and Reichardt, L. F. Trk receptors mediators of neurotrophin action. Curr. Opin. Neurobiol. 11 272-280, 2001. 

CREB is also phosphorylated on serine 133 by stimulation of growth factor signaling cascades [63]. This occurs via a complex pathway involving MAPK cascades (Fig. 23-9). Thus, as outlined earlier, nerve growth factor and related neurotrophins that act on receptor tyrosine kinases lead to the successive activation of Ras, Raf, MEK and ERK. Activated ERK then phosphorylates and activates a serine-threonine kinase, RSK, particular subtypes of which directly activate CREB via the phosphorylation of serine 133. 

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... 

The specific actions of the individual neurotrophins have been the subject of intense interest (Table 27-2). It is now evident, through analysis of animals in which the individual neurotrophin genes or their receptors have been knocked out, that the family members have unique actions acting exclusively to support some neuronal subpopulations [11]. However, in some neuronal populations, the action of several of the neurotrophins overlap. For example, in the peripheral sensory ganglia, individual neurons are responsive to more than one neurotrophin. 

NGF also has actions within the CNS, although it is not particularly abundant in the CNS. Its synthesis appears to be largely restricted to the hippocampus and neocortex, and even in these regions it is present at relatively low concentrations relative to the other neurotrophins. The most prominent population of NGF-responsive neurons expressing TrkA are the basal forebrain cholinergic neurons. The principal projections of these neurons are to the hippocampus and cortex, which conforms with the concept that NGF acts as a target-derived trophic factor in the CNS, just as it does in the peripheral nervous system (PNS). NGF also acts on a subpopulation of cholinergic neurons within the striatum. These interneurons express the NGF receptor, TrkA, and respond to NGF. However, they do not appear to rely entirely on NGF for their survival, and the specific actions of NGF on this neuronal population have not been clearly defined. NGF may also have autocrine actions in the CNS, as some neuronal populations have been identified that express both TrkA and NGF. 

The receptor for NGF is TrkA, a 140 kDa cell surface protein that specifically binds NGF, but not other neurotrophins [5, 6, 9]. TrkA is expressed on the neuronal cell body and on neuronal processes. In its action as a target-derived trophic factor, NGF is secreted within the target organ and it then binds to TrkA receptors present on the growing neuronal process or synapse. The NGF-TrkA complex is then internalized and subsequently translocated to the cell body by retrograde axonal transport. In those cells that respond to NGF through autocrine or paracrine mechanisms, the growth factor can bind to any of the widely distributed TrkA molecules on the neuronal membrane. 

Neurotrophin 4/5 is not as well characterized as other members of the neurotrophin family. Much of what is known is derived from analysis of NT4/5 and TrkB knockout mice. Elucidating the actions of NT4/5 is complicated by virtue of the fact that both NT4/5 and BDNF exert their effects via the TrkB receptor. It appears that NT4/5 functions largely overlap with those of other neurotrophin family members, particularly BDNF. NT4/5 knockout mice are essentially normal, in contrast to BDNF knockout mice, which do not live long. NT4/5 is likely to have unique actions on a subpopulation of neurons in the nodose and geniculate ganglia, which are not supported by BDNF. Like BDNF, NT4/5 acts on sensory neurons and retinal ganglion cells, supporting their survival. 

Dechant G, Rodriguez-Tebar A, Barde Y. 1994. Neurotrophin receptors. Prog Neurobiol 42 347-352. 

Miranda RC, Sohrabji F, Toran-Allerand CD. 1993. Neuronal colocalization of mRNAs for neurotrophins and their receptors in the developing central nervous system suggests a potential for autocrine interactions. Proc Natl Acad Sci USA 90 6439-6443. 

Teng KK, Hempstead BL. 2004. Neurotrophins and their receptors signaling trios in complex biological systems. Cell Mol Life Sci 61 35-48. 

Analytical flow cytometry offers a rapid and facile means of monitoring cellular receptor content. For example, multiparameter flow cytometry techniques were used to monitor expression of GABAa receptor subunits during neurogenesis in embryonic rat brain (Marie et al., 2001). The content of the cell surface p75 neurotrophin receptor was measured in a heterogeneous population of mouse dorsal root sensory neurons, from which high and low p75 subsets were subsequently isolated by cell sorting (Barrett et al., 1998). 

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