The protean actions of neurotrophins and their receptors on the life and death of neurons

doi:10.1016/j.tins.2004.11.003

Trends in Neurosciences

Volume 28, Issue 1, January 2005, Pages 5-11

https://doi.org/10.1016/j.tins.2004.11.003 Get rights and content

At vanishingly low concentrations, factors of the neurotrophin family (NGF, BDNF, NT3 and NT4/5) can promote neuronal survival or death. Many investigations indicate that the survival-promoting signals of neurotrophins are generated by activation of Trk tyrosine kinase receptors and that their death-promoting signals are generated by activation of p75 neurotrophin receptors (p75^NTR). Despite this, a body of work indicates that p75^NTR can promote cell survival and Trk receptors can adversely affect neuron health. The potential mechanisms by which these receptors could have such diverse and antipodal effects are considered here.

Section snippets

The expanding family of neurotrophin receptors and new forms of neurotrophins

At any specific location in the nervous system, the biological actions of a trophic factor will be dominated by the signaling cascade engaged by the receptor with the highest affinity for the ligand. This assumes that all receptors have equal access to the trophic factor, and that this factor is present in non-saturating concentrations. Until relatively recently it was generally understood that neurotrophins utilize two types of receptors to mediate their multifarious actions on neurons. The p75

Signaling modules that guide the life–death decisions of neurons

Many in vitro studies indicate that Trk receptor activation positively affects neuronal function (Figure 1). Survival of sympathetic neurons, for example, requires the continuous activation of trkA 15, 16. These salubrious effects involve the small GTP-binding protein Ras [17] and downstream effectors in the mitogen activated protein (MAP) kinase [18] and phosphatidylinositol 3-kinase (PI3K) [19] pathways. In addition to Ras, the Rap1 small GTP-binding protein is likely to play an important

Unexpected complexity – p75^NTR can promote cell survival and Trk receptors can cause cell death

One could imagine that the neurotrophin receptors have opposite effects on neuronal survival and act independently. According to this view, whether a neuron lives or dies depends on a balancing act wherein the key determinant is the predominance of signaling from one receptor subtype over that from the other. It seems very likely that this view is incorrect, as each receptor can engage survival-promoting or death-promoting signaling pathways. In addition, there is evidence of crosstalk between

Potential mechanisms by which Trk receptors could increase vulnerability to death signals

One of the difficulties with the notion that Trk activation can adversely affect neuronal survival is that we are only beginning to understand how this might occur. Investigations of the signaling cascades downstream from Trk receptor activation implicate the MAP kinase pathway in studies of cortical neurons and the PI3K pathway in studies of spinal cord neurons. But the change in the cellular phenotype that makes neurons die, or become more vulnerable to insult, has eluded identification. The

Spatiotemporal factors and Trk receptor signaling

Two additional factors can importantly influence the nature of neurotrophin actions: location of the signaling event and its temporal pattern [57]. Target-derived neurotrophins can bind to axonal Trk receptors, be endocytosed and undergo retrograde transport as signaling endosomes 58, 59, 60. The capacity to undergo endocytosis appears intimately linked to the survival-promoting actions of activated Trk receptors [61], although there is evidence to the contrary [62]. The signaling pathways

Concluding remarks

Neurotrophin signaling is a multifaceted business and it is at least possible that all the dramatis personne have yet to be identified. Although increasing neurotrophin signaling is being considered as a therapy for neurodegenerative disorders in human patients, this approach is based on several assumptions. Foremost is the belief that Trk receptor signaling is salubrious and that no harm will come from enhancing signaling through this receptor. The validity of this notion is perhaps less

Acknowledgements

I am grateful for the critical review of this manuscript by David Pleasure, Moses Chao and Mark Bothwell. The views expressed herein are solely those of the author. Work in the Kalb Laboratory is supported by the NIH (NS29837), NASA (NAG2–1582), The Spinal Cord Research Foundation (#2069) and the ALS Association.

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Trends in Neurosciences

The protean actions of neurotrophins and their receptors on the life and death of neurons

Section snippets

The expanding family of neurotrophin receptors and new forms of neurotrophins

Signaling modules that guide the life–death decisions of neurons

Unexpected complexity – p75NTR can promote cell survival and Trk receptors can cause cell death

Potential mechanisms by which Trk receptors could increase vulnerability to death signals

Spatiotemporal factors and Trk receptor signaling

Concluding remarks

Acknowledgements

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Unexpected complexity – p75^NTR can promote cell survival and Trk receptors can cause cell death

Biochemical and functional interactions between the neurotrophin receptors trk and p75^NTR