Biochemical and biophysical investigation of the brain-derived neurotrophic factor mimetic 7,8-dihydroxyflavone in the binding and activation of the TrkB receptor.

Academic Article

Abstract

  • 7,8-dihydroxyflavone (7,8-DHF), a newly identified small molecular TrkB receptor agonist, rapidly activates TrkB in both primary neurons and the rodent brain and mimics the physiological functions of the cognate ligand BDNF. Accumulating evidence supports that 7,8-DHF exerts 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 in which TrkB maturation may be implicated. Employing two independent biophysical approaches, we confirm that 7,8-DHF interacts robustly with the TrkB extracellular domain, with a Kd of ∼10 nm. Although 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 for BDNF to elicit the full spectrum of TrkB signaling cascades. Hence, 7,8-DHF interacts robustly with the TrkB receptor, and its agonistic effect may be mediated by neuronal development and maturation.
  • Authors

    Published In

    Keywords

  • 7,8-Dihydroxyflavone, Brain-Derived Neurotrophic Factor (BDNF), Cell Signaling, Cell Surface Receptor, Endocytosis, Phosphorylation, TrkB, Animals, Biophysical Phenomena, Brain-Derived Neurotrophic Factor, Cells, Cultured, Flavones, Humans, Kinetics, Neurons, Protein Binding, Rats, Receptor, trkB
  • Digital Object Identifier (doi)

    Pubmed Id

  • 18528435
  • Author List

  • Liu X; Obianyo O; Chan CB; Huang J; Xue S; Yang JJ; Zeng F; Goodman M; Ye K
  • Start Page

  • 27571
  • End Page

  • 27584
  • Volume

  • 289
  • Issue

  • 40