User talk:Anders Lewisesquerre
From Proteopedia
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Brain-derived neurotrophic factor (BDNF)
Introduction
Brain-derived neurotrophic factor (BDNF) is a 13kDa signaling protein belonging to the neurotrophin family of growth factors. This family of growth factors are critical in the development, differentiation, and survival of neurons. Mammalian members of the neurotrophin family of growth factors include Nerve growth factor (NGF) [structure link], neurotrophin-3 (NT-3) [structure link], and neurotrophin-4/5 (NT-4/5)[structure link]. BDNF is primarily expressed in the brain, where it is found in the hippocampus, cortex, amygdala, and striatum, and less so in the hypothalamus. BDNF is also expressed in peripheral tissues, such as the kidneys, retina, prostate, motor neurons, skeletal muscle.
Function
Brain-derived neurotrophic factor (BDNF) is involved in the growth, differentiation, and survival of neurons in the central, and peripheral nervous systems. It plays a role in neural plasticity, neurogenesis, energy metabolism, inflammation and immunity, neurotransmitter regulation, and potential roles in the cardiovascular system. The role of BDNF in neural plasticity is shown in its ability to regulate NDMA receptor signaling by increasing calcium influx and more BDNF release, which by retrograde signaling, enhances pre-synaptic vesicle cycling, thereby regulating long-term potentiation (LTP), and plasticity.
Mechanism
Effects of the mammalian neurotrophin family of proteins are accomplished through activation of the tropomyosin-related kinase receptor family (TrkA, TrkB, and TrkC), and the p75 neurotrophin receptor, which is a member of the tumor necrosis factor receptor superfamily. Binding to the p75 neurotrophin receptor leads to neurite outgrowth via Trk modulation, and activation of (JNK), which leads to apoptosis. As a reference, the complex formed upon binding of Nerve growth factor (NGF) – a neurotrophin with close structural homology to BDNF – to the p75 receptor is , where NGF is shown in lime, and the p75 receptor is shown in fuchsia. BDNF binds to (TrkB), which results in activation of three different signaling cascades. These signaling pathways cause activation of CREB and CREB-binding protein (CBP), transcription factors which regulate expression of genes involved in neural plasticity, cell survival, and stress resistance. The IRS-1/PI3K/AKT pathway Involves sequential activation of Insulin receptor substrate 1 (IRS1/2), phosphatidylinositol-3-kinase (PI3K), and protein kinase B (Akt). The pathway activates protein kinase A (Akt) which suppresses apoptosis In the Ras/MAPK/ERK pathway, Ras activates the Ras/MAPK/ERK pathway, as well as the PIK3, and PLC pathways. MAPK/ERK promotes cell survival by induction of pro survival genes and inhibition of pro-apoptotic proteins The third cascade is the PLC/DAG/IP3 pathway, where PLC-𝛾 is phosphorylated by BDNF binding to the TrkB receptor, leading to production of IP3 and DAG. IP3 increases intracellular calcium concentrations, and DAG regulates protein kinase C, which is important in the MAPK/ERK pathway.
Structure
BDNF
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Disease
Implicated in multiple neurodegenerative diseases due to its apparent neuroprotective effects, ability to promote neurogenesis, and improve synaptic plasticity. Diseases include parkinson’s disease, Huntington's disease, multiple sclerosis, Alzheimer's disease, dementia, and possibly schizophrenia. BDNF is also associated with type-2 diabetes mellitus by its regulation of energy metabolism, specifically increasing the amount of insulin secreting granules in pancreatic 𝛃 cells through TrkB signal pathways.
