Ryskamp Daniel A, Korban Svetlana, Zhemkov Vladimir, Kraskovskaya Nina, Bezprozvanny Ilya
Department of Physiology, UT Southwestern Medical Center at Dallas, Dallas, TX, United States.
Laboratory of Molecular Neurodegeneration, Peter the Great St. Petersburg State Polytechnic University, Saint Petersburg, Russia.
Front Neurosci. 2019 Aug 28;13:862. doi: 10.3389/fnins.2019.00862. eCollection 2019.
Sigma-1 receptor (S1R) is a multi-functional, ligand-operated protein situated in endoplasmic reticulum (ER) membranes and changes in its function and/or expression have been associated with various neurological disorders including amyotrophic lateral sclerosis/frontotemporal dementia, Alzheimer's (AD) and Huntington's diseases (HD). S1R agonists are broadly neuroprotective and this is achieved through a diversity of S1R-mediated signaling functions that are generally pro-survival and anti-apoptotic; yet, relatively little is known regarding the exact mechanisms of receptor functioning at the molecular level. This review summarizes therapeutically relevant mechanisms by which S1R modulates neurophysiology and implements neuroprotective functions in neurodegenerative diseases. These mechanisms are diverse due to the fact that S1R can bind to and modulate a large range of client proteins, including many ion channels in both ER and plasma membranes. We summarize the effect of S1R on its interaction partners and consider some of the cell type- and disease-specific aspects of these actions. Besides direct protein interactions in the endoplasmic reticulum, S1R is likely to function at the cellular/interorganellar level by altering the activity of several plasmalemmal ion channels through control of trafficking, which may help to reduce excitotoxicity. Moreover, S1R is situated in lipid rafts where it binds cholesterol and regulates lipid and protein trafficking and calcium flux at the mitochondrial-associated membrane (MAM) domain. This may have important implications for MAM stability and function in neurodegenerative diseases as well as cellular bioenergetics. We also summarize the structural and biochemical features of S1R proposed to underlie its activity. In conclusion, S1R is incredibly versatile in its ability to foster neuronal homeostasis in the context of several neurodegenerative disorders.
西格玛-1受体（S1R）是一种位于内质网（ER）膜上的多功能配体激活蛋白，其功能和/或表达的变化与多种神经疾病相关，包括肌萎缩侧索硬化症/额颞叶痴呆、阿尔茨海默病（AD）和亨廷顿舞蹈病（HD）。S1R激动剂具有广泛的神经保护作用，这是通过多种S1R介导的信号功能实现的，这些功能通常具有促生存和抗凋亡作用；然而，关于该受体在分子水平上的确切作用机制，人们了解相对较少。本综述总结了S1R调节神经生理学并在神经退行性疾病中发挥神经保护功能的治疗相关机制。这些机制多种多样，因为S1R可以结合并调节大量的客户蛋白，包括内质网和质膜中的许多离子通道。我们总结了S1R对其相互作用伙伴的影响，并考虑了这些作用在细胞类型和疾病特异性方面的一些情况。除了在内质网中的直接蛋白质相互作用外，S1R可能通过控制转运来改变几种质膜离子通道的活性，从而在细胞/细胞器水平发挥作用，这可能有助于降低兴奋性毒性。此外，S1R位于脂筏中，在那里它结合胆固醇并调节线粒体相关膜（MAM）结构域的脂质和蛋白质转运以及钙通量。这可能对神经退行性疾病中MAM的稳定性和功能以及细胞生物能量学具有重要意义。我们还总结了被认为是S1R活性基础的结构和生化特征。总之，在几种神经退行性疾病的背景下S1R在促进神经元稳态方面具有令人难以置信的多功能性。
