Function and Mechanisms of Truncated BDNF Receptor TrkB.T1 in Neuropathic Pain

Abstract

Brain-derived neurotrophic factor (BDNF), a major focus for regenerative therapeutics, has been lauded for its pro-survival characteristics and involvement in both development and recovery of function within the central nervous system (CNS). However, studies of tyrosine receptor kinase B (TrkB), a major receptor for BDNF, indicate that certain effects of the TrkB receptor in response to disease or injury may be maladaptive. More specifically, imbalance among TrkB receptor isoforms appears to contribute to aberrant signaling and hyperpathic pain. A truncated isoform of the receptor, TrkB.T1, lacks the intracellular kinase domain of the full length receptor and is up-regulated in multiple CNS injury models. Such up-regulation is associated with hyperpathic pain, and TrkB.T1 inhibition reduces neuropathic pain in various experimental paradigms. Deletion of TrkB.T1 also limits astrocyte changes in vitro, including proliferation, migration, and activation. Mechanistically, TrkB.T1 is believed to act through release of intracellular calcium in astrocytes, as well as through interactions with neurotrophins, leading to cell cycle activation. Together, these studies support a potential role for astrocytic TrkB.T1 in hyperpathic pain and suggest that targeted strategies directed at this receptor may have therapeutic potential.

Neuronal, but not glial, Contactin 2 negatively regulates axon regeneration in the injured adult optic nerve

“…Truncated TrkB has identical extracellular and transmembrane domains to the full‐length receptor but lacks the cytoplasmic region containing the catalytic tyrosine kinase domain (Klein et al., 1990). It is expressed in various cell types and plays important roles in dendritogenesis and synaptogenesis during development, while it is up‐regulated in multiple CNS injury models, a process associated with hyperpathic pain (Cao et al., 2020; Luberg et al., 2010). Truncated TrkB is known to act as a dominant negative inhibitor of the full‐length TrkB and prevents subsequent activation of downstream signalling pathways mediating cell proliferation and survival, including the PI3K/Akt pathway (Baxter et al., 1997; Eide et al., 1996; Fenner, 2012; Haapasalo et al., 2001).…”

Brain‑derived neurotrophic factor in autoimmune inflammatory diseases (Review)

“…In general, gp145TrkB activation triggers three downstream tyrosine kinase-mediated pathways, PLCγ1/PKC, MAPK-ERK and PI3/Akt, which regulate cell survival and differentiation ( 25 ). On the contrary, the truncated gp95TrkB, devoid of the tyrosine kinase domain, has a negative effect, which binds and internalizes BDNF without autophosphorylation ( 26 ). Of note, truncated gp95trkB may still mediate BDNF-induced cell proliferation but the mechanism has remained elusive.…”

Peptides Derived from Growth Factors to Treat Alzheimer’s Disease

“…This inhibition induces cytoskeletal rearrangement in neuronal cells [ 82 ]. However, the truncated Trk signaling and function in normal brain and neuropathologic conditions are complex and still under investigation (for a review, see [ 84 ]).…”