Biochemical and Biophysical Investigation of Brain-derived Neurotrophic Factor Mimetic 7,8-Dihydroxyflavone in Binding and Activation of TrkB Receptor [Neurobiology]

August 20th, 2014 by Liu, X., Obianyo, O., Chan, C. B., Huang, J., Xue, S., Yang, J., Zheng, F., Goodman, M., Ye, K.

7,8-dihydroxyflavone (7,8-DHF), a newly identified small molecular TrkB receptor agonist, rapidly activates TrkB in both primary neurons and rodent brain and mimics the physiological functions of the cognate ligand BDNF. Accumulative evidence supports that 7,8-DHF exerts the neurotrophic effects in a TrkB-dependent manner; nonetheless, the differences between 7,8-DHF and BDNF in activating TrkB remain incompletely understood. Here we show that 7,8-DHF and BDNF exhibit different TrkB activation kinetics, for which TrkB maturation may be implicated. Employing two independent biophysical approaches, we confirm that 7,8-DHF robustly interacts with the TrkB extracellular domain (ECD) with a Kd of approximately 10 nM. While BDNF transiently activates TrkB, leading to receptor internalization and ubiquitination/degradation, in contrast, 7,8-DHF-triggered TrkB phosphorylation lasts for hours, and the internalized receptors are not degraded. Notably, primary neuronal maturation may be required for 7,8-DHF but not BDNF to elicit the full spectrum of TrkB signaling cascades. Hence, 7,8-DHF robustly interacts with the TrkB receptor and its agonistic effect may be mediated by neuronal development and maturation.
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