Mechanisms and regulation of neurotrophin synthesis and secretion

Abstract

Neurotrophins are secreted proteins that are synthesized as pre-pro-neurotrophins on the rough endoplasmic reticulum, which are subsequently processed and then secreted as mature proteins. During synthesis, neurotrophins are sorted in the trans-Golgi apparatus into 2 pathways of secretion; the constitutive and the regulated pathways. Neurotrophins in the constitutive pathway are secreted cautiously without any trigger, while in the regulated pathway of secretion an external stimulus elevates the calcium concentration intracellularly leading to neurotrophin release. The regulation of sorting and secretion of neurotrophins is critical for several processes in the body, such as synaptic plasticity, neurodegenerative disorders, demyelination disease, and inflammation. The purpose of this review is to summarize the current mechanisms of neurotrophin sorting and secretion.

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⁺