Functional interactions between steroid hormones and neurotrophin BDNF

Figure 1 Brain-derived neurotrophic factor (BDNF) gene and stimulated intracellular signaling cascades after activation of tropomyosin-related kinase (Trk)B. A: Mouse and rat BDNF genes (we referred to the description by Aid et al[15]). Each BDNF transcript is comprised of one of eight 5’ untranslated exons (exon I-VIII) and the common 3’ protein coding exon IX; B: Intracellular signaling after TrkB activation. Following BDNF binding, TrkB dimerization and its phosphorylation at intracellular tyrosine residues occur. Then, the activated TrkB stimulates three main signaling pathways: (1) mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK); (2) phosphatidylinositol 3-kinase (PI3K); and (3) phospholipase Cγ (PLCγ) pathways. MAPK pathway, in which MAPK/ERK kinase (MEK) is involved, plays a role in the neuronal differentiation and outgrowth. PI3K signaling promotes neuronal survival via Ras or GRB-associated binder 1 (Gab1). Following PLCγ activation, inositol-1,4,5-trisphosphate (IP₃) and diacylglycerol (DAG) are both produced. DAG activates protein kinase C (PKC), which is important for regulation of synaptic plasticity. Meanwhile, IP₃ increases intracellular Ca²⁺ concentration via IP₃ receptors on the endoplasmic reticulum (ER), resulting in activation of Ca²⁺/calmodulin (CaM)-dependent protein kinase including CaMKII, CaMKK, and CaMKI. These MAPK/ERK, PI3K, and PLCγ pathways can regulate gene transcription.