Regulation of TrkB cell surface expression-a mechanism for modulation of neuronal responsiveness to brain-derived neurotrophic factor

Andreska T, Lüningschrör P, Sendtner M.
Cell Tissue Res.

Review article


Neurotrophin signaling via receptor tyrosine kinases is essential for the development and function of the nervous system in vertebrates. TrkB activation and signaling show substantial differences to other receptor tyrosine kinases of the Trk family that mediate the responses to nerve growth factor and neurotrophin-3. Growing evidence suggests that TrkB cell surface expression is highly regulated and determines the sensitivity of neurons to brain-derived neurotrophic factor (BDNF). This translocation of TrkB depends on co-factors and modulators of cAMP levels, N-glycosylation, and receptor transactivation. This process can occur in very short time periods and the resulting rapid modulation of target cell sensitivity to BDNF could represent a mechanism for fine-tuning of synaptic plasticity and communication in complex neuronal networks. This review focuses on those modulatory mechanisms in neurons that regulate responsiveness to BDNF via control of TrkB surface expression.

Published: Oct 2020

Figure 1
Schematic representation of cAMP-mediated TrkB surface translocation via PKA/PI3K. Neuronal activity triggers Ca2+ entry via AMPA and NMDA receptors (a). Ca2+ stimulates adenylyl cyclase activity followed by elevation of cAMP levels which trigger PKA and PI3K activity (b). Rapidly available intracellular reserve pools of TrkB are mobilized in a microtubule-dependent manner (c). TrkB containing vesicles are transported to distinct target sites at the cell surface, like dendritic spines where they integrate. In the dendritic target area, TrkB is transported via Myosin Va in an actin-dependent manner and associates with PSD-95 which promotes guided transport and integration into the PSD (d). At the cell surface, TrkB is sensitive for BDNF binding which activates TrkB via phosphorylation at C-terminal tyrosine residues (e)