Lu B, Pang PT, Woo NH 2005. The yin and yang of neurotrophin action

Mature neurotrophins bind preferentially to Trk receptor tyrosine kinases. By contrast, proneurotrophins (neurotrophin precursors) bind with high affinity to the p75 neurotrophin receptor (p75NTR). Interaction of mature neurotrophins with Trk receptors leads to cell survival, whereas binding of pro-nerve growth factor (proNGF) to p75NTR leads to apoptosis. The 'yin and yang' effects of neurotrophins are, therefore, controlled by the proteolytic cleavage of proneurotrophins. Proneurotrophins can be cleaved intracellularly by furin or prohormone convertases 1 and 2 (PC1/2), and extracellularly by proteases such as tissue plasminogen activator (tPA)/plasmin and matrix metalloproteinases 3 and 7 (MMP3/7). NGF is secreted mainly in the mature form, whereas brain-derived neurotrophic factor (BDNF) is secreted predominantly in the pro- form. The pro-domain of BDNF is involved in the correct folding and intracellular trafficking of BDNF. The mature domain of BDNF contains a structural motif that interacts with the sorting receptor carboxypeptidase E (CPE) to sort BDNF into the regulated secretory pathway. In the hippocampus, BDNF has 'yin and yang' effects on long-term synaptic plasticity by activating p75NTR and TrkB, respectively. Mature BDNF facilitates hippocampal early-phase long-term potentiation (E-LTP) through presynaptic mechanisms. In addition, the conversion of pro- to mature BDNF by the tPA/plasmin system is crucial for the expression of late-phase LTP (L-LTP) at hippocampal synapses. ProBDNF, on the other hand, selectively promotes the NMDA (N-methyl-D-aspartate)-receptor-dependent form of long-term depression (LTD) in the hippocampus. This is achieved by p75NTR-mediated expression of NR2B, a subunit of the NMDA receptor that is uniquely involved in LTD. Studying yin–yang aspects of neurotrophin function should generate important advances in our understanding of how neurotrophins regulate bidirectional processes at the cellular level, and how this affects a range of cognitive processes.