Brain-derived neurotrophic factor (BDNF) is a neurotrophin, which is essential for growth, differentiation, plasticity, and survival of neurons. BDNF is also required for processes such as energy metabolism, behavior, mental health, learning, memory, stress, pain and apoptosis. BDNF is implicated in various neuronal disorders such as Alzheimer’s disease, Huntington’s disease, depression, and bipolar disorder .
BDNF binds to tropomyosin-related kinase B (TrkB), which is a tyrosine kinase receptor . It also binds with low affinity to p75 neurotrophin receptor (p75NTR) . BDNF and its receptors are expressed throughout the central and peripheral nervous system ,.
BDNF signaling is elicited when it dimerizes and binds to TrkB, which results in the receptor dimerization and autophosphorylation . The activation of the receptor results in its interaction with molecules such as Shp2 , Shc and PLC-gamma . These molecules further interact and modify their downstream targets leading to various neuronal processes. BDNF signaling activates the signaling cascades such as PLC/PKC, PI3K/Akt, Ras/Erk, AMPK/ACC and NFB pathways. BDNF activates PLC/PKC pathway, which leads to release of intracellular calcium  and regulation of synaptic plasticity . Activation of PI3K/Akt pathway through BDNF-TrkB interaction inhibits cell apoptosis by decreasing the expression of BIM . However, BDNF-p75NTR interaction leads to apoptosis through JNK pathway . PI3K/Akt also leads to activation of mTOR pathway and subsequently protein synthesis . Ras/Erk signaling is involved in cell proliferation, differentiation and protection of neurons . BDNF signaling leads to nitric oxide production through NFB pathway . It activates Rac and Cdc42 leading to increased neurite outgrowth . It enhances oxidation of fat through AMPK mediated inhibition of ACC . BDNF also regulates the expression of genes leading to processes such as differentiation of dendrites and calcification of cementoblast-like cells .
1. Binder DK, Scharfman HE: Brain-derived neurotrophic factor. Growth Factors 2004; 22:123-131.
2. Martin-Zanca D, Hughes SH, Barbacid M: A human oncogene formed by the fusion of truncated tropomyosin and protein tyrosine kinase sequences. Nature 1986; 319:743-748.
3. Chao MV, Bothwell MA, Ross AH, Koprowski H, Lanahan AA, Buck CR, Sehgal A: Gene transfer and molecular cloning of the human NGF receptor. Science 1986; 232:518-521.
4. Leibrock J, Lottspeich F, Hohn A, Hofer M, Hengerer B, Masiakowski P, Thoenen H, Barde YA: Molecular cloning and expression of brain-derived neurotrophic factor. Nature 1989; 341:149-152.
5. Allen SJ, Dawbarn D, Eckford SD, Wilcock GK, Ashcroft M, Colebrook SM, Feeney R, MacGowan SH: Cloning of a non-catalytic form of human trkB and distribution of messenger RNA for trkB in human brain. Neuroscience 1994; 60:825-834.
6. Klein R, Nanduri V, Jing SA, Lamballe F, Tapley P, Bryant S, Cordon-Cardo C, Jones KR, Reichardt LF, Barbacid M: The trkB tyrosine protein kinase is a receptor for brain-derived neurotrophic factor and neurotrophin-3. Cell 1991; 66:395-403.
7. Wu K, Xu JL, Suen PC, Levine E, Huang YY, Mount HT, Lin SY, Black IB: Functional trkB neurotrophin receptors are intrinsic components of the adult brain postsynaptic density. Brain Res Mol Brain Res 1996; 43:286-290.
8. Yamada M, Ohnishi H, Sano S, Araki T, Nakatani A, Ikeuchi T, Hatanaka H: Brain-derived neurotrophic factor stimulates interactions of Shp2 with phosphatidylinositol 3-kinase and Grb2 in cultured cerebral cortical neurons. J Neurochem 1999; 73:41-49.
9. Yamada M, Numakawa T, Koshimizu H, Tanabe K, Wada K, Koizumi S, Hatanaka H: Distinct usages of phospholipase C gamma and Shc in intracellular signaling stimulated by neurotrophins. Brain Res 2002; 955:183-190.
10. Finkbeiner S, Tavazoie SF, Maloratsky A, Jacobs KM, Harris KM, Greenberg ME: CREB: a major mediator of neuronal neurotrophin responses. Neuron 1997; 19:1031-1047.
11. Groth RD, Mermelstein PG: Brain-derived neurotrophic factor activation of NFAT (nuclear factor of activated T-cells)-dependent transcription: a role for the transcription factor NFATc4 in neurotrophin-mediated gene expression. J Neurosci 2003; 23:8125-8134.
12. Zhu W, Bijur GN, Styles NA, Li X: Regulation of FOXO3a by brain-derived neurotrophic factor in differentiated human SH-SY5Y neuroblastoma cells. Brain Res Mol Brain Res 2004; 126:45-56.
13. Yeiser EC, Rutkoski NJ, Naito A, Inoue J, Carter BD: Neurotrophin signaling through the p75 receptor is deficient in traf6-/- mice. J Neurosci 2004; 24:10521-10529.
14. Kenchappa RS, Tep C, Korade Z, Urra S, Bronfman FC, Yoon SO, Carter BD: p75 neurotrophin receptor-mediated apoptosis in sympathetic neurons involves a biphasic activation of JNK and up-regulation of tumor necrosis factor-alpha-converting enzyme/ADAM17. J Biol Chem 2010; 285:20358-20368.
15. Szatmari E, Kalita KB, Kharebava G, Hetman M: Role of kinase suppressor of Ras-1 in neuronal survival signaling by extracellular signal-regulated kinase 1/2. J Neurosci 2007; 27:11389-11400.
16. Burke MA, Bothwell M: p75 neurotrophin receptor mediates neurotrophin activation of NF-kappa B and induction of iNOS expression in P19 neurons. J Neurobiol 2003; 55:191-203.
17. Miyamoto Y, Yamauchi J, Tanoue A, Wu C, Mobley WC: TrkB binds and tyrosine-phosphorylates Tiam1, leading to activation of Rac1 and induction of changes in cellular morphology. Proc Natl Acad Sci U S A 2006; 103:10444-10449.
18. Matthews VB, Astrom MB, Chan MH, Bruce CR, Krabbe KS, Prelovsek O, Akerstrom T, Yfanti C, Broholm C, Mortensen OH, Penkowa M, Hojman P, Zankari A, Watt MJ, Bruunsgaard H, Pedersen BK, Febbraio MA: Brain-derived neurotrophic factor is produced by skeletal muscle cells in response to contraction and enhances fat oxidation via activation of AMP-activated protein kinase. Diabetologia 2009; 52:1409-1418.
19. Kajiya M, Shiba H, Fujita T, Ouhara K, Takeda K, Mizuno N, Kawaguchi H, Kitagawa M, Takata T, Tsuji K, Kurihara H: Brain-derived neurotrophic factor stimulates bone/cementum-related protein gene expression in cementoblasts. J Biol Chem 2008; 283:16259-16267.