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The yin and yang of neurotrophin action

Key Points

  • 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.

Abstract

Neurotrophins have diverse functions in the CNS. Initially synthesized as precursors (proneurotrophins), they are cleaved to produce mature proteins, which promote neuronal survival and enhance synaptic plasticity by activating Trk receptor tyrosine kinases. Recent studies indicate that proneurotrophins serve as signalling molecules by interacting with the p75 neurotrophin receptor (p75NTR). Interestingly, proneurotrophins often have biological effects that oppose those of mature neurotrophins. Therefore, the proteolytic cleavage of proneurotrophins represents a mechanism that controls the direction of action of neurotrophins. New insights into the 'yin and yang' of neurotrophin activity have profound implications for our understanding of the role of neurotrophins in a wide range of cellular processes.

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Figure 1: The yin and yang of neurotrophin receptors and neurotrophin function.
Figure 2: The synthesis and sorting of BDNF.
Figure 3: The yin and yang of long-term synaptic regulation by pro- and mature BDNF

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Acknowledgements

N.H.W. is supported by fellowships from the Alberta Heritage Foundation for Medical Research and Natural Sciences and the Engineering Research Council of Canada. We thank Lucas Pozzo-Miller and members of the Lu laboratory for comments.

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DATABASES

Entrez Gene

Akt

BAD

BCL2

BDNF

CPE

CREB

GluR1

MMP3

MMP7

NGF

NR2B

NT3

NT4

PI3K

p75NTR

sortilin

tPA

TrkA

TrkB

TrkC

FURTHER INFORMATION

Bai Lu's homepage

Glossary

REGULATED SECRETION

A cellular process in which the fusion of vesicles, and secretion of their protein contents, is triggered by extracellular signals.

LARGE DENSE CORE VESICLE (LDCV).

A secretory vesicle that contains protein or peptide. Under the electron microscope, a large dense core can be seen at the centre of the vesicle.

PRO-OPIOMELANOCORTIN (POMC).

A peptide precursor that gives rise to various neuropeptides through protease cleavage. Pro-opiomelanocortin is known to contain a three-dimensional sorting motif that interacts with the sorting receptor CPE to direct it to the regulated secretory pathway.

CONSTITUTIVE SECRETION

A cellular process in which vesicles spontaneously fuse with the plasma membrane to release their protein contents into the extracellular space.

DOMINANT-NEGATIVE

A mutant molecule that can form a heteromeric complex with the normal molecule, knocking out the activity of the entire complex.

LIPID RAFT

A dynamic assembly of cholesterol and sphingolipids in the plasma membrane.

TETANIC STIMULATION

A train of stimuli in which afferent axons are briefly activated at high frequency. In LTP experiments, a 1-s train of pulses delivered at a frequency of 100 Hz is commonly used to potentiate transmission.

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Lu, B., Pang, P. & Woo, N. The yin and yang of neurotrophin action. Nat Rev Neurosci 6, 603–614 (2005). https://doi.org/10.1038/nrn1726

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