A novel ligand-controlled endoplasmic reticulum chaperone sigma-1 receptor regulates the intracellular processing of brain-derived neurotrophic factor

Tuesday, October 25, 2011 — Poster Session II
Noon – 2:00 p.m.	Natcher Conference Center	NIDA	CELLBIO-3

Authors

• M Fujimoto
• T Hayashi
• R Urfer
• S Mita
• TP Su

Abstract

Brain-derived neurotrophic factor (BDNF) is a multi-functional neurotrophin that regulates neuronal survival, differentiation, and neuronal transmission. The secretion of BDNF is regulated in multiple steps including glycosylation, folding, sorting, cleavage, and secretion. However, mechanisms underlying the intracellular processing of BDNF remain to be totally clarified. Here, we found that the endoplasmic reticulum (ER) chaperone sigma-1 receptor (Sig-1R) modulates the secretion of BDNF. In this study, we employed rat neuroblastoma B104 cells because of the high efficacy of those cells in the processing and secretion of BDNF. A selective Sig-1R agonist cutamesine (SA4503) that has been shown to improve memory, promote cell survival, and is currently in phase II clinical trials for major depression and post-stroke recovery was tested for its effect on BDNF secretion. Cutamesine (0.1-10 μM, 7 days) dose- and time-dependently increased endogenous BDNF in the culture medium; the effect was abolished by a selective Sig-1R antagonist NE-100. In B104 cells overexpressing BDNF, cutamesine decreased both pro- and cleaved BDNF inside cells, whereas increased mature BDNF in culture medium, indicating cutamesine facilitates the processing and secretion of BDNF. Thus, targeting the ER machinery by Sig-1R ligands may offer a new approach to the treatment of neuropsychiatric diseases.

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