F281, synthetic agonist of the sigma-2 receptor, induces Ca²⁺ efflux from the endoplasmic reticulum and mitochondria in SK-N-SH cells

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• 作者：Giuseppe Cassano ; Giuseppe Gasparre ; Mauro Niso ; Marialess ; ra Contino ; Vito Scalera ; Nicola Antonio Colabufo
• 关键词：Endoplasmic reticulum ; Mitochondria ; Neuromodulation ; Receptor ; Tumour
• 刊名：Cell Calcium
• 出版年：2009
• 出版时间：April 2009
• 年：2009
• 卷：45
• 期：4
• 页码：340-345
• 全文大小：412 K

文摘

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 tumour 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 μM, 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.