Pharmacological Regulation of Endoplasmic Reticulum Structure and Calcium Dynamics: Importance for Neurodegenerative Diseases.

IF 19.3 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pharmacological Reviews Pub Date : 2023-09-01 DOI:10.1124/pharmrev.122.000701
Ilmari Parkkinen, Anna Their, Muhammad Yasir Asghar, Sreesha Sree, Eija Jokitalo, Mikko Airavaara
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引用次数: 2

Abstract

The endoplasmic reticulum (ER) is the largest organelle of the cell, composed of a continuous network of sheets and tubules, and is involved in protein, calcium (Ca2+), and lipid homeostasis. In neurons, the ER extends throughout the cell, both somal and axodendritic compartments, and is highly important for neuronal functions. A third of the proteome of a cell, secreted and membrane-bound proteins, are processed within the ER lumen and most of these proteins are vital for neuronal activity. The brain itself is high in lipid content, and many structural lipids are produced, in part, by the ER. Cholesterol and steroid synthesis are strictly regulated in the ER of the blood-brain barrier protected brain cells. The high Ca2+ level in the ER lumen and low cytosolic concentration is needed for Ca2+-based intracellular signaling, for synaptic signaling and Ca2+ waves, and for preparing proteins for correct folding in the presence of high Ca2+ concentrations to cope with the high concentrations of extracellular milieu. Particularly, ER Ca2+ is controlled in axodendritic areas for proper neurito- and synaptogenesis and synaptic plasticity and remodeling. In this review, we cover the physiologic functions of the neuronal ER and discuss it in context of common neurodegenerative diseases, focusing on pharmacological regulation of ER Ca2+ Furthermore, we postulate that heterogeneity of the ER, its protein folding capacity, and ensuring Ca2+ regulation are crucial factors for the aging and selective vulnerability of neurons in various neurodegenerative diseases. SIGNIFICANCE STATEMENT: Endoplasmic reticulum (ER) Ca2+ regulators are promising therapeutic targets for degenerative diseases for which efficacious drug therapies do not exist. The use of pharmacological probes targeting maintenance and restoration of ER Ca2+ can provide restoration of protein homeostasis (e.g., folding of complex plasma membrane signaling receptors) and slow down the degeneration process of neurons.

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内质网结构和钙动力学的药理调节:对神经退行性疾病的重要性。
内质网(ER)是细胞中最大的细胞器,由片状和小管组成的连续网络,参与蛋白质、钙(Ca2+)和脂质稳态。在神经元中,内质网延伸到整个细胞,包括染色体和轴突隔室,对神经元功能非常重要。细胞蛋白质组的三分之一,分泌和膜结合蛋白,在内质网管内处理,其中大多数蛋白质对神经元活动至关重要。大脑本身脂质含量很高,许多结构性脂质部分是由内质网产生的。胆固醇和类固醇的合成在受血脑屏障保护的脑细胞内质网中受到严格的调节。内质网腔内的高Ca2+水平和低细胞质浓度是基于Ca2+的细胞内信号,突触信号和Ca2+波,以及在高Ca2+浓度存在下为正确折叠准备蛋白质以应对高浓度的细胞外环境所需要的。特别是,内质网Ca2+在轴突区域受到控制,以实现适当的神经和突触发生以及突触的可塑性和重塑。在这篇综述中,我们涵盖了神经元内质网的生理功能,并在常见的神经退行性疾病的背景下讨论了它,重点是内质网Ca2+的药理调节。此外,我们假设内质网的异质性、其蛋白质折叠能力和确保Ca2+调节是各种神经退行性疾病中神经元衰老和选择性易感性的关键因素。意义声明:内质网(ER) Ca2+调节剂是目前尚无有效药物治疗的退行性疾病的有希望的治疗靶点。使用靶向ER Ca2+维持和恢复的药理学探针可以恢复蛋白质稳态(例如,复杂质膜信号受体的折叠)并减缓神经元的变性过程。
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来源期刊
Pharmacological Reviews
Pharmacological Reviews 医学-药学
CiteScore
34.70
自引率
0.50%
发文量
40
期刊介绍: Pharmacological Reviews is a highly popular and well-received journal that has a long and rich history of success. It was first published in 1949 and is currently published bimonthly online by the American Society for Pharmacology and Experimental Therapeutics. The journal is indexed or abstracted by various databases, including Biological Abstracts, BIOSIS Previews Database, Biosciences Information Service, Current Contents/Life Sciences, EMBASE/Excerpta Medica, Index Medicus, Index to Scientific Reviews, Medical Documentation Service, Reference Update, Research Alerts, Science Citation Index, and SciSearch. Pharmacological Reviews offers comprehensive reviews of new pharmacological fields and is able to stay up-to-date with published content. Overall, it is highly regarded by scholars.
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