title: Brain derived neurotrophic factor is involved in the regulation of glycogen synthase kinase 3β (GSK3β) signalling.
abstract: Glycogen synthase kinase 3β (GSK3β) is involved in several biochemical processes in neurons regulating cellular survival, gene expression, cell fate determination, metabolism and proliferation. GSK3β activity is inhibited through the phosphorylation of its Ser-9 residue. In this study we sought to investigate the role of BDNF/TrkB signalling in the modulation of GSK3β activity. BDNF/TrkB signalling regulates the GSK3β activity both in vivo in the retinal tissue as well as in the neuronal cells under culture conditions. We report here for the first time that BDNF can also regulate GSK3β activity independent of its effects through the TrkB receptor signalling. Knockdown of BDNF lead to a decline in GSK3β phosphorylation without having a detectable effect on the TrkB activity or its downstream effectors Akt and Erk1/2. Treatment with TrkB receptor agonist had a stimulating effect on the GSK3β phosphorylation, but the effect was significantly less pronounced in the cells in which BDNF was knocked down. The use of TrkB receptor antagonist similarly, manifested itself in the form of downregulation of GSK3β phosphorylation, but a combined TrkB inhibition and BDNF knockdown exhibited a much stronger negative effect. In vivo, we observed reduced levels of GSK3β phosphorylation in the retinal tissues of the BDNF(+/-) animals implicating critical role of BDNF in the regulation of the GSK3β activity. Concluding, BDNF/TrkB axis strongly regulates the GSK3β activity and BDNF also exhibits GSK3β regulatory effect independent of its actions through the TrkB receptor signalling.
authors.affiliation: Australian School of Advanced Medicine, Macquarie University, Australia. Electronic address: vivek.gupta@mq.edu.au.
authors.forename: Vivek
authors.initials: V
authors.lastname: Gupta
authors.affiliation: Australian School of Advanced Medicine, Macquarie University, Australia.
authors.forename: Nitin
authors.initials: N
authors.lastname: Chitranshi
authors.affiliation: Australian School of Advanced Medicine, Macquarie University, Australia.
authors.forename: Yuyi
authors.initials: Y
authors.lastname: You
authors.affiliation: School of Medical Sciences, Edith Cowan University, Perth, Australia.
authors.forename: Veer
authors.initials: V
authors.lastname: Gupta
authors.affiliation: Australian School of Advanced Medicine, Macquarie University, Australia; Save Sight Institute, Sydney University, Sydney, Australia.
authors.forename: Alexander
authors.initials: A
authors.lastname: Klistorner
authors.affiliation: Australian School of Advanced Medicine, Macquarie University, Australia; Save Sight Institute, Sydney University, Sydney, Australia.
authors.forename: Stuart
authors.initials: S
authors.lastname: Graham
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004789:Enzyme Activation; D005260:Female; D017353:Gene Deletion; D055785:Gene Knockdown Techniques; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism*; D008297:Male; D051379:Mice; D016716:PC12 Cells; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D011505:Protein-Tyrosine Kinases; D000071679:Glycogen Synthase Kinase 3 beta
keywords: 7,8 Dihydroxyflavone; Brain-derived neurotrophic factor; Glycogen synthase kinase 3β; Protein phosphorylation; TrkB receptor