The sigma-1 receptor antagonist PB212 reduces the Ca²⁺-release through the inositol (1, 4, 5)-trisphosphate receptor in SK-N-SH cells

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• 作者：Giuseppe Gasparre^a ; Carmen Abate^b ; Francesco Berardi^b ; Giuseppe Cassano^a ; ^{cassano@biologia.uniba.it}
• 关键词：Endoplasmic reticulum ; Mitochondria ; Neuromodulation ; Receptor ; Tumor
• 刊名：European Journal of Pharmacology
• 出版年：2012
• 期刊代码：24_00142999
• 类别：neu
• 出版时间：5 June, 2012
• 卷：684
• 期：1-3
• 页码：59-63
• 文件大小：506 K

摘要

Sigma-1 receptors are specifically located at the endoplasmic reticulum-mitochondrion interface, but upon stimulation by ligands or under prolonged cellular stress, they translocate to other areas of the cell. Sigma-1 receptors are involved in the regulation of intracellular [Ca²⁺] by affecting the Ca²⁺-influx or the release from intracellular stores. In SK-N-SH cells, we measured the affinity of 4-methyl-1-[4-(6-methoxynaphthalen-1-yl)butyl]piperidine (PB212) at sigma-1 receptor by using a competition binding assay with specific radioligand; we obtained a K_i value = 316 卤 19 nM. PB212 also showed an antiproliferative effect in SK-N-SH cells (EC₅₀ = 32 卤 4 渭M) but had no effect in MCF7 cells, which only express sigma-2 receptor; these findings suggest that PB212 behaves as a sigma-1 receptor antagonist. We have studied the effect of PB212 on Ca²⁺ homeostasis of the SK-N-SH cell line with the fluorescent probe Fura-2. 100 渭M PB212 induced a Ca²⁺-efflux from the endoplasmic reticulum through the inositol (1, 4, 5)-trisphosphate (IP₃) receptor. Moreover, [PB212] ranging from 1 to 100 渭M reduced the Ca²⁺-response, triggered by carbachol or bradykinin that engage the phospholipase C/IP₃ pathway; such a response is generally increased by sigma-1 receptor agonists. On the other hand, PB212 did not reduce the Ca²⁺-response mediated by IP₃ in LoVo cells, which do not express neither sigma-1 nor sigma-2 receptors, and in MCF7 cells. The fact that the activity of the sigma-1 receptor can be experimentally modulated by agonists and antagonists supports the intriguing hypothesis that some endogenous molecules, unknown at the moment, modulate the sigma-1 receptor and its cellular targets.