CHAPTER 49 – The Mechanism of NGF Suggested by the NGF–TrkA-D5 Complex

Nerve growth factor (NGF) is the founding member of the neurotrophins, a family of growth factors responsible for the formation and maintenance (survival or apoptosis) of neuronal populations in the peripheral and central nervous system. The neurotrophins are of potential therapeutic interest in a number of neurological disorders such as Alzheimer's and Parkinson's diseases. In addition to NGF, the neurotrophin family includes brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4/5 (NT-4/5), and neurotrophin-6 (NT-6). These molecules exert their biological activities through binding to two unrelated classes of receptors. One of these, the p75 neurotrophin receptor (p75 NTR ), also referred to as the low-affinity receptor, binds to all neurotrophins with nanomolar affinity and is responsible for their apoptotic activities. The Trks, or so-called high-affinity receptors, are more specific and mediate the trophic effects of neurotrophins through dimerization-induced tyrosine kinase activity. TrkA binds to NGF (and weakly to NT-3), TrkB to BDNF and NT-4/5 (and weakly to NT-3), and TrkC binds to NT-3. The presence on the same cell of both p75 NTR and TrkA results in high-affinity binding sites with picomolar affinities for NGF [2].