BDNF signaling pathway

Brain-derived neurotrophic factor (BDNF) is a neurotrophin 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 tyrosine kinase receptor known as tropomyosin-related kinase B (TrkB). 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, resulting 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 activates the signaling cascades such as PLC/PKC, PI3K/Akt, Ras/Erk, AMPK/ACC and NFκB pathways. BDNF through PLC/PKC pathway leads to release of intracellular calcium and regulation of synaptic plasticity. It also maintains synaptic plasticity through cAMP/PKA signaling. Activation of PI3K/Akt pathway through BDNF/TrkB interaction inhibits cell apoptosis by decreasing the expression of BIM. However, BDNF/p75NTR interaction activates JNK through TRAF6, which leads to apoptosis. Activation of JNK3 also leads to proteolytic cleavage of the p75NTR by TACE. 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 also leads to neuronal survival through Erk5/Mef pathway. Phosphorylation of synapsin by Erk1/2 leads to neurotransmitter release. BDNF signaling leads to nitric oxide production through NFκB pathway. BDNF induces neurite outgrowth through activation of JAK/STAT, Rac, and Cdc42 pathways. BDNF enhances oxidation of fat through AMPK mediated inhibition of ACC. It also plays role in microtubule assembly through inhibition of GSK3-beta. It leads to oxidative neuronal necrosis through activation of NCF molecules. BDNF also regulates the surface expression of AMPA and NMDA receptors. BDNF also regulates the expression of genes leading to processes such as differentiation of dendrites and calcification of cementoblast-like cells.

脑源性神经营养因子（BDNF）是一种对神经元生长、分化、可塑性和存活至关重要的神经营养素。BDNF亦参与诸如能量代谢、行为、心理健康、学习、记忆、压力、疼痛及细胞凋亡等过程。BDNF与神经元疾病如阿尔茨海默病、亨廷顿病、抑郁症和双相情感障碍等密切相关。BDNF与名为肌动蛋白相关激酶B（TrkB）的酪氨酸激酶受体结合，同时以较低亲和力与p75神经营养素受体（p75NTR）结合。BDNF及其受体在中央和周围神经系统广泛表达。当BDNF二聚化并与TrkB结合时，引发受体的二聚化和自磷酸化，从而触发BDNF信号通路。受体的激活导致其与Shp2、Shc和PLC-γ等分子相互作用。这些分子进一步相互作用并修饰其下游靶标，引发多种神经元过程。BDNF通过PLC/PKC、PI3K/Akt、Ras/Erk、AMPK/ACC和NFκB信号通路激活信号级联反应。BDNF通过PLC/PKC通路导致细胞内钙离子的释放和突触可塑性的调节。它还通过cAMP/PKA信号通路维持突触可塑性。BDNF通过BDNF/TrkB相互作用激活PI3K/Akt通路，通过降低BIM的表达抑制细胞凋亡。然而，BDNF/p75NTR相互作用通过TRAF6激活JNK，导致细胞凋亡。JNK3的激活还导致TACE对p75NTR的蛋白水解切割。PI3K/Akt还导致mTOR通路的激活和随后的蛋白质合成。Ras/Erk信号通路涉及细胞增殖、分化和神经元保护。BDNF还通过Erk5/Mef通路导致神经元存活。Erk1/2对突触素的磷酸化导致神经递质释放。BDNF通过NFκB通路导致一氧化氮的产生。BDNF通过激活JAK/STAT、Rac和Cdc42通路诱导神经突生长。BDNF通过AMPK介导的ACC抑制增强脂肪的氧化。它还通过抑制GSK3-β在微管组装中发挥作用。它通过激活NCF分子导致氧化性神经元坏死。BDNF还调节AMPA和NMDA受体的表面表达。BDNF还调节导致如树突分化、成骨细胞样细胞钙化的基因表达。