F281, synthetic agonist of the sigma-2 receptor, induces Ca2+ efflux from the endoplasmic reticulum and mitochondria in SK-N-SH cells
F281, synthetic agonist of the sigma-2 receptor, induces Ca2+ efflux from the endoplasmic reticulum and mitochondria in SK-N-SH cells
复制标题
DOI：
10.1016/j.ceca.2008.12.005
复制
发表时间：
2009-04-01
期刊：
影响因子：
4
通讯作者：
Colabufo, Nicola Antonio
中科院分区：
文献类型：
--
作者：
Cassano, Giuseppe;Gasparre, Giuseppe;Colabufo, Nicola Antonio
我们证明，F281，一种合成的sigma-2受体（s2 R）激动剂，诱导SK-N-SH细胞内[Ca 2 +]（[Ca 2 +]（i））的非瞬时增加和细胞死亡。σ受体分为两种亚型，具有不同的分子量和组织分布。虽然sigma-1受体已被克隆，但s2 r的特征较少，其生理配体和作用需要进一步研究。在turnout细胞系中，s2 R的合成激动剂触发细胞凋亡并调节[Ca 2 +]（i）。特别地，CB-64 D诱导Ca 2+响应，而PB 28抑制Ca 2+信号传导。我们最近合成了F281，通过用咔唑核取代PB 28的5-甲氧基四氢萘部分。尽管这种生物电子等排取代不应影响受体的配体亲和力，但在SK-N-SH细胞中，F281（孵育24小时后）比PB 28更具细胞毒性（EC 50值分别为65.4 nM和8.13 μ M）。我们使用荧光探针fura-2、rhod-2和JC-1。F281通过打开其肌醇1，4，5-三磷酸受体从线粒体和内质网中动员Ca 2 +;还观察到通过由储存耗尽激活的通道的Ca 2+进入。在[Ca 2 +]（i）增加后10分钟内，我们观察到代谢活性和细胞内[ATP]突然下降，导致细胞死亡。(C)2009爱思唯尔有限公司保留所有权利。
We demonstrate that F281, a synthetic agonist of the sigma-2 receptor (s2R), induces a non transient increase in intracellular [Ca2+] ([Ca2+](i)) and cell death in SK-N-SH cells. Sigma receptors are classified into two subtypes, with different molecular weight and tissue distribution. While the sigma-1 receptor has been cloned, the s2r is less characterized and its physiological ligand and role need further investigation. In turnout cell lines, synthetic agonists of the s2R trigger apoptosis and modulate [Ca2+](i). In particular, CB-64D induces a Ca2+ response while PB28 supresses Ca2+ signalling. We have recently synthesized F281, by replacing the 5-methoxytetraline moiety of PB28 with a carbazole nucleus. Although this bioisosteric substitution should not affect the ligand affinity at the receptor, F281 (after 24 h incubation) was more cytotoxic than PB28 (EC50 values 65.4 nM and 8.13 mu M, respectively) in SK-N-SH cells. We used the fluorescent probes fura-2, rhod-2 and JC-1. F281 mobilizes Ca2+ from mitochondria and from the endoplasmic reticulum, by opening its inositol 1,4,5-trisphosphate receptor; Ca2+-entry through the channels activated by store depletion was also observed. After the increase in [Ca2+](i) and within 10 min, we observed a sudden drop in metabolic activity and intracellular [ATP] leading to cell death. (C) 2009 Elsevier Ltd. All rights reserved.