PDF(Pubmed)
Abstract：
Sigma-1 receptor (S1R) is a calcium-sensitive, ligand-operated receptor chaperone present on the endoplasmic reticulum (ER) membrane. S1R plays an important role in ER-mitochondrial inter-organelle calcium signaling and cell survival. S1R and its agonists confer resilience against various neurodegenerative diseases; however, the molecular mechanism of S1R is not yet fully understood. At resting state, S1R is either in a monomeric or oligomeric state but the ratio of these concentrations seems to change upon activation of S1R. S1R is activated by either cellular stress, such as ER-calcium depletion, or ligands. While the effect of ligands on S1R quaternary structure remains unclear, the effect of cellular stress has not been studied. In this study we utilize cellular and an in-vivo model to study changes in quaternary structure of S1R upon activation. We incubated cells with cellular stressors (H2O2 and thapsigargin) or exogenous ligands, then quantified monomeric and oligomeric forms. We observed that benzomorphan-based S1R agonists induce monomerization of S1R and decrease oligomerization, which was confirmed in the liver tissue of mice injected with (+)-Pentazocine. Antagonists block this effect but do not induce any changes when used alone. Oxidative stress (H2O2) increases the monomeric/oligomeric S1R ratio whereas ER calcium depletion (thapsigargin) has no effect. We also analyzed the oligomerization ability of various truncated S1R fragments and identified the fragments favorizing oligomerization. In this publication we demonstrate that quaternary structural changes differ according to the mechanism of S1R activation. Therefore, we offer a novel perspective on S1R activation as a nuanced phenomenon dependent on the type of stimulus.
摘要：
Sigma-1受体(S1R)是一种钙敏感型,配体操作的受体分子伴侣存在于内质网（ER）膜上。S1R在ER-线粒体细胞器间钙信号传导和细胞存活中起重要作用。S1R及其激动剂赋予对各种神经退行性疾病的抵抗力；然而，S1R的分子机制尚未完全了解。在静止状态,S1R处于单体或寡聚状态,但这些浓度的比率似乎在S1R活化时发生变化。S1R被细胞应激激活，例如ER-钙消耗，或配体。虽然配体对S1R四级结构的影响尚不清楚，细胞应激的影响尚未被研究。在这项研究中，我们利用细胞和体内模型来研究S1R激活后四级结构的变化。我们用细胞应激源（H2O2和thapsigargin）或外源配体孵育细胞，然后定量单体和寡聚形式。我们观察到基于苯并吗啡的S1R激动剂诱导S1R的单体化并减少寡聚化，这在注射（+）-喷他佐辛的小鼠的肝组织中得到证实。拮抗剂阻断这种作用,但当单独使用时不诱导任何变化。氧化应激（H2O2）增加了单体/寡聚S1R的比例，而ER钙消耗（thapsigargin）没有影响。我们还分析了各种截短的S1R片段的寡聚化能力,并鉴定了有利于寡聚化的片段。在该出版物中，我们证明了四级结构变化根据S1R激活的机制而有所不同。因此,我们提供了一个关于S1R激活的新观点，这是一种取决于刺激类型的细微现象。
