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Figures
- Figure 1
Neurotrophin synthesis and sorting. Neurotrophins are synthesized as pre-pro-neurotrophins on the rough endoplasmic reticulum (ER) and then move to the golgi apparatus to accumulate in the trans-Golgi network (TGN). In the TGN, neurotrophins are sorted to either the constitutive secretory vesicles or the regulated secretory granules. Sortilin and carboxypeptidase E (CPE) are important sorting receptors that mediate neurotrophins targeting to the regulated secretory granules. BDNF - brain derived neurotrophic factor, mRNA - messenger ribonucleic acid
- Figure 2
The mechanisms of regulated neurotrophin secretion. Neurotrophins secretion relies on elevation of intracellular Ca2+ concentration. The Ca2+ influx through voltage gated calcium channels (VGCC) and/or NMDA receptor upon depolarization and Ca2+ release from IP3R in response to metabotropic glutamate receptor (mGLUR) activation causes an increase in intracellular Ca2+. The Ca2+ influx induces Ca2+ release from ryanodine receptors (RyR), which amplifies the CA2+ rise. The Ca2+ activates calcium calmodulin kinase II (CaMKII) inducing the fusion of the secretory vesicles in a mechanism involving the protein kinase A (PKA) action. Secreted neurotrophins act in a positive feedback mechanism to augment intracellular Ca2+ rise. Activation of PKG via the nitric oxide (NO) signaling pathway down-regulate neurotrophins secretion by desensitizing many proteins involved in the release process. Trk - tropomyosin-related kinase, PLC -phospholypase C, IP3- inositol 1, 4, 5-trisphosphate, IP3R- IP3-receptor, sGC- soluble guanylyl cyclase, PKG- protein kinase G, Na+ - Sodium, AMPA-a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, NMDA - The N-methyl-D-aspartate receptor, Dep - depolarization, Ca2+ - calcium2+
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