title: Biochemical and biophysical investigation of the brain-derived neurotrophic factor mimetic 7,8-dihydroxyflavone in the binding and activation of the TrkB receptor.
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.affiliation: From the Departments of Pathology and Laboratory Medicine and.
authors.forename: Xia
authors.initials: X
authors.lastname: Liu
authors.affiliation: From the Departments of Pathology and Laboratory Medicine and.
authors.forename: Obiamaka
authors.initials: O
authors.lastname: Obianyo
authors.affiliation: From the Departments of Pathology and Laboratory Medicine and.
authors.forename: Chi Bun
authors.initials: CB
authors.lastname: Chan
authors.affiliation: From the Departments of Pathology and Laboratory Medicine and.
authors.forename: Junjian
authors.initials: J
authors.lastname: Huang
authors.affiliation: the Departments of Chemistry and Biology, Center for Diagnostics and Therapeutics (CDT), Georgia State University, Atlanta, Georgia 30303.
authors.forename: Shenghui
authors.initials: S
authors.lastname: Xue
authors.affiliation: the Departments of Chemistry and Biology, Center for Diagnostics and Therapeutics (CDT), Georgia State University, Atlanta, Georgia 30303.
authors.forename: Jenny J
authors.initials: JJ
authors.lastname: Yang
authors.affiliation: Radiology and Imaging Sciences, Psychiatry, and Hematology and Oncology, Center for Systems Imaging, Wesley Woods Health Centers, Emory University School of Medicine, Atlanta, Georgia 30322 and.
authors.forename: Fanxing
authors.initials: F
authors.lastname: Zeng
authors.affiliation: Radiology and Imaging Sciences, Psychiatry, and Hematology and Oncology, Center for Systems Imaging, Wesley Woods Health Centers, Emory University School of Medicine, Atlanta, Georgia 30322 and.
authors.forename: Mark
authors.initials: M
authors.lastname: Goodman
authors.affiliation: From the Departments of Pathology and Laboratory Medicine and kye@emory.edu.
authors.forename: Keqiang
authors.initials: K
authors.lastname: Ye
mesh_terms: D000818:Animals; D055592:Biophysical Phenomena; D019208:Brain-Derived Neurotrophic Factor / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D047309:Flavones / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D009474:Neurons / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D020813:Receptor, trkB / Q000819:agonists / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: C485383:6,7-dihydroxyflavone; D019208:Brain-Derived Neurotrophic Factor; D047309:Flavones; D020813:Receptor, trkB
keywords: 7,8-Dihydroxyflavone; Brain-Derived Neurotrophic Factor (BDNF); Cell Signaling; Cell Surface Receptor; Endocytosis; Phosphorylation; TrkB