HOME :: CHAPTER 13 :: THE NEUROTROPHIN RECEPTORS :: NEUROTROPHIN RECEPTORS

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). Each provides some survival activity on nervous tissue. As mentioned in the text, the final number of neurons innervating a particular organ is attained by thinning the population of neurons through programmed neuronal death. Here, neurotrophic factors secreted by cells in the target field protect the neurons from apoptosis (Korsching, 1993; Lewin and Barde, 1996). Thus, the final number of neurons innervating a target reflects the availability of neurotrophins. The ability of particular neural subsets to respond only to particular neurotrophins can explain the losses of certain peripheral sympathetic neurons in NGF-knockout mice, the deficiency of sensory neurons in BDNF knockout mice, the lack of proprioceptive neurons in NT-3 knockout mice, and the deficiency of particular sensory neurons in NT-4 knockout mice. Neurotrophins also play roles in regulating neuronal plasticity and in regulating the number of neural progenitor cells.

Neurotrophin receptors:

There are two classes of neurotrophin cell-surface receptors. The p75 receptor (also known as the low-affinity neurotrophin receptor, LANR) is common to all members of the neurotrophin family. The high affinity receptors (having binding constants on the order of 10^-11) include receptor tyrosine kinase proteins TrkA, TrkB, and TrkC. These receptors have different specificities for different members of the neurotrophin family (Figure 1).

Figure 1 Neurotrophins and their preferred receptors are shown with bold arrows. The dashed arrows indicate weak interactions. All neutrophins bind to p75. After Waartiovarra, GDNF and p75 neurotrophin receptor in development and disease.

TrkA is the receptor for NGF, trkB is the receptor for BDNF and NT-4, and trkC is the receptor for NT-3. However, NT-3 can also bind to trkA and trkB, but with lower affinity than to trkC, and with lower affinity than the primary ligands for these receptors. Similarly, NT-4 also binds to trkA but with lower affinity.

In addition to these "classical" receptors, the issue is complicated by the existence of isoforms of trkB and trkC, which lack the cytoplasmic tyrosine kinase catalytic region (Barbacid, 1995). These receptors are found throughout the developing body as well, and it is not known if these noncatalytic forms of the receptors act as agonists or inhibitors.

All four neurotrophins also bind to the low affinity nerve growth factor receptor, p75. The p75 receptor belongs to the tumor necrosis factor receptor family and was the first identified neurotrophin receptor (Johnson et al; 1986). This receptor will bind the neurotrophins, but it has no cytoplasmic tyrosine kinase domain (Chao and Hempstead, 1995; Greene and Kaplan, 1995; Segal and Greenberg, 1996). The roles of this receptor are controversial, as it may also be involved in either promoting or downregulating the response to the neurotrophin. P75 may function to increase the affinity of the trk receptors for their respective neurotrophins, or it may bind the neurotrophins and prevent them from binding to the high affinity receptors. Although it does not have a catalytic intracellular tyrosine kinase domain, it is capable of mediating the neurotrophin signals. The ligand binding of p75 increases the high-affinity TrkA binding sites, enhances TrkA autophosphorylation and selectivity for neurotrophin ligands (Kaplan and Miller, 1997). P75 also increases intracellular ceramide levels and further activates NFk B transcription factor (Carter et al., 1996) and JNK kinase (Casaccia-Bonnefil et al., 1996) independently of tyrosine kinase activity. Conversely, TrkA activation can inhibit p75-mediated signaling, but the mechanism of this inhibition is unclear (Kaplan and Miller, 1997).

The TrkA neurotrophin receptor has been linked to human diseases. The TrkA gene was originally described as an oncogene in colon cancer (Martin-Zanca et al., 1986) and its translocations are common in papillary thyroid carcinoma (Bongarzone et al., 1989). Recently, a mutation in the TrkA gene was found to cause congenital insensitivity to pain with anhidrosis (CIPA) syndrome (Indo et al., 1996) that closely resembles the phenotype of the TrkA -deficient mice. No disease associations have been described either for the TrkB gene, or the genes for p75NTR or any of the neurotrophins.

For beautiful models of the trk receptor and p75 receptor, go to the neurotrophin website.

Literature Cited

Bongarzone, I., Pierotti, M. A., Monzini, N., Mondellini, P., Manenti, G., Donghi, R., Pilotti, S., Grieco, M., Santoro, M., Fusco, A., et al. 1989. High frequency of activation of tyrosine kinase oncogenes in human papillary thyroid carcinoma. Oncogene 4: 1457-1462.

Carter, B. D., Kaltschmidt, C., Kaltschmidt, B., Offenhauser, N., Bohm-Matthaei, R., Baeuerle, P. A., and Barde, Y. A. 1996. Selective activation of NF-kappa B by nerve growth factor through the neurotrophin receptor p75. Science 272: 542-545.

Casaccia-Bonnefil, P., Carter, B. D., Dobrowsky, R. T., and Chao, M. V. 1996. Death of oligodendrocytes mediated by the interaction of nerve growth factor with its receptor p75. Nature 383: 716-719.

Chao, M. V. and Hempstead, B. L. 1995. p75 and Trk: a two-receptor system. Trends Neurosciences 18: 321-326.

Greene, L. A. and Kaplan, D. R. (1995). Early events in neurotrophin signalling via Trk and p75 receptors. Current Opinion in Neurobiology 5: 579-587.

Indo, Y., Tsuruta, M., Hayashida, Y., Karim, M. A., Ohta, K., Kawano, T., Mitsubuchi, H., Tonoki, H., Awaya, Y., and Matsuda, I. (1996). Mutations in the TRKA/NGF receptor gene in patients with congenital insensitivity to pain with anhidrosis. Nature Genetics 13, 485-488.

Johnson D., Lanahan A., Buck, C. R., Sehgal A., Morgan, C., Mercer, E., Bothwell, M., and Chao, M. 1986. Expression and structure of the human NGF receptor. Cell 47:545-554.

Kaplan, D. R. and Miller, F. D. 1997. Signal transduction by the neurotrophin receptors. Current Opinion in Cell Biology 9: 213-221.

Korsching, S. 1993. The neurotrophic factor concept: a reexamination. J. Neuroscience 13: 2739-2748.

Lewin, G. R. and Barde, Y. A. 1996. Physiology of the neurotrophins. Annu. Rev. Neuroscience 19: 289-317.

Martin-Zanca, D., Hughes, S. H., and Barbacid, M. 1986. A human oncogene formed by the fusion of truncated tropomyosin and protein tyrosine kinase sequences. Nature 319: 743-748.

Segal, R. A. and Greenberg, M. E. 1996. Intracellular signaling pathways activated by neurotrophic factors. Annu. Rev. Neuroscience 19: 463-489.

© All the material on this website is protected by copyright. It may not be reproduced in any form without permission from the copyright holder.

HOME :: CHAPTER 13 :: THE NEUROTROPHIN RECEPTORS :: NEUROTROPHIN RECEPTORS

PREVIOUS :: NEXT