Ilmari Parkkinen, Anna Their, Muhammad Yasir Asghar, Sreesha Sree, Eija Jokitalo, Mikko Airavaara
{"title":"Pharmacological Regulation of Endoplasmic Reticulum Structure and Calcium Dynamics: Importance for Neurodegenerative Diseases.","authors":"Ilmari Parkkinen, Anna Their, Muhammad Yasir Asghar, Sreesha Sree, Eija Jokitalo, Mikko Airavaara","doi":"10.1124/pharmrev.122.000701","DOIUrl":null,"url":null,"abstract":"<p><p>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 (Ca<sup>2+</sup>), 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 Ca<sup>2+</sup> level in the ER lumen and low cytosolic concentration is needed for Ca<sup>2+</sup>-based intracellular signaling, for synaptic signaling and Ca<sup>2+</sup> waves, and for preparing proteins for correct folding in the presence of high Ca<sup>2+</sup> concentrations to cope with the high concentrations of extracellular milieu. Particularly, ER Ca<sup>2+</sup> 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 Ca<sup>2+</sup> Furthermore, we postulate that heterogeneity of the ER, its protein folding capacity, and ensuring Ca<sup>2+</sup> regulation are crucial factors for the aging and selective vulnerability of neurons in various neurodegenerative diseases. SIGNIFICANCE STATEMENT: Endoplasmic reticulum (ER) Ca<sup>2+</sup> 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 Ca<sup>2+</sup> can provide restoration of protein homeostasis (e.g., folding of complex plasma membrane signaling receptors) and slow down the degeneration process of neurons.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"75 5","pages":"959-978"},"PeriodicalIF":19.3000,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"2","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Pharmacological Reviews","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1124/pharmrev.122.000701","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
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.
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.