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. 2018 Jul 11;72(9):633–653. doi: 10.1111/pcn.12683

Figure 4.

Figure 4

Brain‐derived neurotrophic factor (BDNF)/tropomyosin kinase receptor B (TrkB) pathway. BDNF is synthesized as a precursor protein (pro‐BDNF) that is proteolytically processed into mature BDNF by intracellular proteases and/or extracellular proteases.159, 160, 161 Synthesis, release, and action of BDNF are regulated by neuronal activity. BDNF mRNA increases after neuron depolarization162 and BDNF levels are mediated by calcium‐calmodulin‐dependent protein kinases (CaMK).163 TrkB is a tyrosine kinase membrane protein highly expressed in both presynaptic axons and postsynaptic densities.164, 165, 166 TrkB activation promotes spine formation, neuronal survival, and long‐term potentiation.167, 168, 169, 170, 171 TrkB consists of the following three main domains: an extracellular domain where the ligand (usually BDNF) binds, a transmembrane domain, and a cytosolic domain, which contains the catalytic sites that are responsible for a transphosphorylation reaction.172 Binding of BDNF to the recognition site increases its affinity for the TrkB monomer, stabilizing to form a TrkB dimer.173 This dimerization activates the catalytic sites, and each TrkB phosphorylates the other on specific tyrosine residues (Y706).174 Secondary messenger molecules (such as sarc homology containing [Shc] and phospholipase C gamma [PLCγ]) bind to the phospho‐tyrosines in positions 515 (Y515) and 816 (Y816) and activate the Ras/Erk and PIP3/Ca+2 dependent pathways, respectively. The latter pathway leads to activation of protein kinase C (PKC) and eventually to the phosphorylation of cyclic AMP response element binding protein (CREB).175 CREB in turn induces gene expression involved in neuroplasticity.176, 177, 178, 179, 180, 181, 182 Neuronal activation and high‐frequency stimulation facilitate the localization of TrkB from intracellular pools to the cell surface, requiring a Ca+2 influx.183 Akt, cellular homolog of murine thymoma virus akt8 oncogene; CBP, CREB‐binding protein; ERK, extracellular signal‐regulated kinase; P, phosphorylation.