TrkB receptor signalling: implications in neurodegenerative, psychiatric and proliferative disorders

Abstract

The Trk family of receptors play a wide variety of roles in physiological and disease processes in both neuronal and non-neuronal tissues. Amongst these the TrkB receptor in particular has attracted major attention due to its critical role in signalling for brain derived neurotrophic factor (BDNF), neurotrophin-3 (NT3) and neurotrophin-4 (NT4). TrkB signalling is indispensable for the survival, development and synaptic plasticity of several subtypes of neurons in the nervous system. Substantial evidence has emerged over the last decade about the involvement of aberrant TrkB signalling and its compromise in various neuropsychiatric and degenerative conditions. Unusual changes in TrkB signalling pathway have also been observed and implicated in a range of cancers. Variations in TrkB pathway have been observed in obesity and hyperphagia related disorders as well. Both BDNF and TrkB have been shown to play critical roles in the survival of retinal ganglion cells in the retina. The ability to specifically modulate TrkB signalling can be critical in various pathological scenarios associated with this pathway. In this review, we discuss the mechanisms underlying TrkB signalling, disease implications and explore plausible ameliorative or preventive approaches.

Figure 1

Schematic representation of the BDNF/TrkB receptor signalling axis and its downstream cellular effects. The binding of neurotrophic factors leads to auto-phosphorylation of the receptor intracellular domain. Cross-talk with other receptors and its regulation is shown. The internalization and transport of BDNF/TrkB in cells through endosomes is represented diagrammatically. P, Phosphorylation; Cav, Caveolin; IP3, Inositol tri-phosphate; CaM, Calmodulin.

Figure 2

TrkB signalling alterations in various disease conditions. An increase (right) or decrease (left) of TrkB expression or its signalling may lead to a range of pathological conditions indicating the significance of the maintenance of a fine equilibrium of the TrkB signalling pathway. TrkB (space-filled)-BDNF (wire-frame) dimeric complex. AD, Alzheimer’s Disease; HD, Huntington’s Disease; PD, Parkinson’s Disease; SIDS, Sudden Infant Death Syndrome; RGC, Retinal Ganglion Cell; MS, Multiple Sclerosis; SCC, Squamous Cell Carcinoma.